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Abnormal expression of circRNAs has been observed in different types of carcinomas, and they play significant roles in the biology of these cancers. Nevertheless, the clinical relevance and functional mechanisms of the majority of circRNAs implicated in breast cancer progression remain unclear. The primary objective of our investigation is to uncover new circRNAs in breast cancer and elucidate the underlying mechanisms by which they exert their effects. The circRNA expression profile data for breast cancer and RNA-sequencing data were acquired from distinct public databases. Differentially expressed circRNAs and mRNA were identified through fold change filtering. The establishment of the competing endogenous RNAs (ceRNAs) network relied on the interplay between circular RNAs, miRNAs, and mRNAs. The hub genes were identified from the protein–protein interaction (PPI) regulatory network using the CytoHubba plugin in Cytoscape. Moreover, the expression levels and prognostic value of these hub genes in the PPI network were assessed using the GEPIA and Kaplan–Meier plotter databases. Fluorescence in situ hybridization (FISH) was used to identified the expression and intracellular localization of hsa_circ_0059665 by using the tissue microarray. Transwell analysis and CCK-8 analysis were performed to assess the invasion, migration, and proliferation abilities of breast cancer cells. Additionally, we investigated the interactions between hsa_circ_0059665 and miR-602 through various methods, including FISH, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assay. Rescue experiments were conducted to determine the potential regulatory role of hsa_circ_0059665 in breast cancer progression. A total of 252 differentially expressed circRNAs were identified. Among them, 246 circRNAs were up-regulated, while 6 circRNAs were down-regulated. Based on prediction and screening of circRNA-miRNA and miRNA-mRNA binding sites, we constructed a network consisting of circRNA-miRNA-mRNA interactions. In addition, we constructed a Protein–Protein Interaction (PPI) network and identified six hub genes. Moreover, the expression levels of these six hub genes in breast cancer tissues were found to be significantly lower. Furthermore, the survival analysis results revealed a significant correlation between low expression levels of KIT, FGF2, NTRK2, CAV1, LEP and poorer prognosis in breast cancer patients. The FISH experiment results indicated that hsa_circ_0059665 exhibits significant downregulation in breast cancer, and its decreased expression is linked to poor prognosis in breast cancer patients. Functional in vitro experiments revealed that overexpression of hsa_circ_0059665 can inhibit proliferation, migration and invasion abilities of breast cancer cells. Further molecular mechanism studies showed that hsa_circ_0059665 exerts its anticancer gene role by acting as a molecular sponge for miR-602. In our study, we constructed and analyzed a circRNA-related ceRNA regulatory network and found that hsa_circ_0059665 can act as a sponge for miR-602 and inhibit the proliferation, invasion and migration of breast cancer cells. [ABSTRACT FROM AUTHOR]

Leukemia inhibitory factor (LIF) is involved in the progression of different cancers. In this study, we investigated the effect of anti-LIF antibodies on immune-related gene expression in the Balb/c mouse model of breast cancer. To immunize mice against LIF, recombinant LIF with Freund adjuvant was injected into the test group, whereas the control group received phosphate-buffered saline with adjuvant. Tumor induction (4T1 cell line) was performed by increasing the antibody titer. The expression of immune-related genes was evaluated by real-time PCR. The anti-LIF titer was significantly increased in the immunized group. The expression of genes related to the differentiation of T helper (Th)-1, Th-2, and Th-17 cells was significantly higher in the immunized group than in the control group. In addition, anti-LIF did not have a significant effect on the expression of genes related to the differentiation of regulatory T cells, and immune checkpoint-associated genes. Additionally, the test group had higher survival and lower tumor development rates. The results demonstrated that the anti-LIF antibody may potentially play a role in the differentiation of immune cells or immune responses. However, further studies utilizing advanced techniques are necessary to validate its function. [ABSTRACT FROM AUTHOR]

Among developed countries, breast carcinoma is one of the most common cancers in women. Breast carcinoma is the result of the fusion of several biological structures, each with its own physiological characteristics and clinical repercussions. The Ficus genus has been reported to have important pharmacological properties in a variety of plants. The current study examined at the anti-mammary action of Ficus glomerata leaf column elute (FGLCE) in 12-Dimethylbenz (α) anthracene (DMBA) driven breast cancer and the mechanism behind it. To produce tumors in female rats, a single dosage of DMBA (25 mg/kg) was injected into the mammary gland. The female rats were divided into five groups- Group I. Control group; Group II- control + FGLCE (100mg/kg of BW); Group III- DMBA treated rats; Group IV- DMBA + FGLCE treated; Group V- DMBA + DOX (5 mg/kg) treated rats. Tumor burden, incidence, and volume were measured at the end of the experiment.The lipid profile (TC, FFA, PL, and TG) in plasma, liver tissue, and mammary tissue were all calculated.At a dose of 25 mg/kg body weight, DMBA inhibits the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPX).DMBA at a dose concentration 25mg/ kg body weight xenobiotic markers increased in group III rats When compared to the control group and glycoprotein p53, and TNF-α, the dosedependent treatment with FGLCE (P<0.05) significantly reduced .Hepatic markers such as alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), tumor necrosis factor- (TNF-α), and inflammatory mediators such as nuclear factor kappa-B(NF-kB) were considerably (P<0.05) down regulated by FGLCE. FGLCE significantly (P<0.05) reduced apoptotic regulator (Bax), B-cell lymphoma 2 (Bcl-2), and Breast Cancer gene 1 (BRCA-1) expression when compared to DMBA control group rats.Therefore, the findings suggest that FGLCE has a protective effect against DMBA-induced mammary gland in rats. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most common cancers and a significant cause of death in females worldwide. For effective breast cancer treatment, using systems with a promising delivery of anticancer agents is an important strategy. Peptide 18 (P18), a tumorhoming peptide, shows a high binding affinity toward breast cancer cells. Nanoliposomes are known to have enhanced accumulation ability in tumors with longer systemic circulation. In this study, Poly (2-ethyl-2-oxazoline) (PEtOx) polymers conjugated with DOPE are used to prepare PEtOx-DOPE nanoliposomes. BikDD, a mutant form of the Bik gene and a member of the BH3-only proapoptotic genes, mimics the constitutively phosphorylated form of the gene. To the best of our knowledge, this study presents a novel approach by investigating P18-conjugated PEtOx-DOPE nanoliposomes (P18-PEtOx-DOPE) for the targeted delivery of BikDD to the AU565 breast cancer model. A site-directed mutated BikDD was loaded into P18-PEtOx-DOPE nanoliposomes, and the targeted drug delivery system was assessed in in vitro and in vivo breast cancer models for efficiency, safety, and efficacy. The increased Bik mRNA expression levels in AU565 cells suggest a high effectiveness of the targeting PEtOx-DOPE nanoliposomes. Following the in vitro studies, the delivery of BikDD by P18-PEtOx-DOPE nanoliposomes was analyzed in CD-1 nude mice models. The animal study showed no significant difference in the tumor volume of the CD-1 nude mice treated with P18-PEtOx-DOPE-BikDD nanoliposomes compared to the free delivery of BikDD. Our preclinical studies suggest that P18-PEtOx-DOPE-BikDD nanoliposomes may be promising gene carriers for targeted breast cancer therapy. Thus, further studies should be carried out to determine the prolonged use of this drug delivery system in breast cancer therapy. [ABSTRACT FROM AUTHOR]

The geometric median, which is applicable to high-dimensional data, can be viewed as a generalization of the univariate median used in 1-dimensional data. It can be used as a robust estimator for identifying the location of multi-dimensional data and has a wide range of applications in real-world scenarios. This paper explores the problem of high-dimensional multivariate analysis of variance (MANOVA) using the geometric median. A maximum-type statistic that relies on the differences between the geometric medians among various groups is introduced. The distribution of the new test statistic is derived under the null hypothesis using Gaussian approximations, and its consistency under the alternative hypothesis is established. To approximate the distribution of the new statistic in high dimensions, a wild bootstrap algorithm is proposed and theoretically justified. Through simulation studies conducted across a variety of dimensions, sample sizes, and data-generating models, we demonstrate the finite-sample performance of our geometric median-based MANOVA method. Additionally, we implement the proposed approach to analyze a breast cancer gene expression dataset. [ABSTRACT FROM AUTHOR]

To screen the target genes that are associated with survival of breast cancer (BRCA) and explore their prognostic values and immune correlations with BRCA using multiple databases.. The microarray expression datasets of BRCA were downloaded from the Gene Expresssion Omnibus database (GEO) and analyzed to obtain differentially expressed genes (DEGs). Hub genes were obtained by constructing and visualizing the protein-protein interaction network of DEGs. The key gene was determined using R language, STRING, and Cytoscape, and the differential expression of the key gene was verified using external datasets The Cancer Genome Atlas (TCGA) and quantitative real-time PCR (qRT-PCR) for BRCA tissues of 37 patients. The prognostic value and immunological correlation of UBE2C in BRCA were explored using R language, TIMER, and Gene Set Enrichment Analysis (GSEA). Of 10 hub genes seleceed from 302 DEGS, UBE2C was identified as the gene associated with BRCA survival. The expression of UBE2C was differentially upregulated in BRCA, as verified by TCGA and qRT-PCR. Prognostic analysis revealed that UBE2C served as an independent prognostic factor. High expression of UBE2C was associated with decreased immune infiltration levels of B cells, CD4+ T cells, CD8+ T cells, macrophages, and myeloid dendritic cells in BRCA tissue. The expression of UBE2C in BRCA showed a significant correlation with immune checkpoints genes PDCD1 , CD274 , and CTLA4 expressions. There was a positive correlation between the expression of UBE2C and the tumor mutational burden and microsatellite instability. GSEA demonstrated that UBE2C expression significantly enriched 786 immune-related gene sets. UBE2C expression in BRCA tissues is closely related to the BRCA immune microenvironment and showes predictive values on the survivals and prognosis of BRCA patients and the effecacy of immunotherapy. UBE2C may be an potential immune-related prognostic biomarker for BRCA. [ABSTRACT FROM AUTHOR]

Aim: Although BRCA1/2 is most frequently associated with hereditary breast and ovarian cancer (HBOC), many other related genes have been implicated. Therefore, we investigated the prevalence of non‐BRCA1/2 genes associated with hereditary cancer predisposition in BRCA1/2‐negative patients from the Department of Genetic Medicine and Services with breast and ovarian cancer using a multi‐gene panel (MGP) analysis. Methods: We conducted a retrospective MGP analysis (National Cancer Center Onco‐Panel for Familial Cancer; NOP_FC) in BRCA1/2‐negative patients with breast, ovarian, and overlapping breast/ovarian cancers who visited our genetic counseling between April 2004 and October 2022. Results: NOP_FC was performed in 128 of the 390 BRCA test‐negative cases (117 breast cancer, 9 ovarian cancer, and 2 overlapping breast/ovarian cancer cases). Among the BRCA1/2‐negative patients, nine (7.7%) with breast cancer and one (11%) with ovarian cancer had pathogenic variants (PVs) in non‐BRCA1/2 genes associated with breast and ovarian cancers, respectively. Five patients had PVs in RAD51D, two in PALB2, one in BARD1, one in ATM, and one in RAD51C. Conclusions: Additional MGP testing of germline genes associated with hereditary cancer predisposition syndrome in BRCA1/2‐negative breast and ovarian cancer patients revealed PVs in non‐BRCA1/2 breast cancer‐ and ovarian cancer‐related genes in 7.7% of breast cancer and 11% of ovarian cancer. Therefore, additional testing may provide useful information for subsequent risk‐reducing surgery and surveillance in BRCA1/2‐negative patients. [ABSTRACT FROM AUTHOR]

Introduction: DNA methylation plays an important role in the carcinogenesis, progression, and prognosis of various human cancers. RASSF1A, BRCA1, APC, and p16 are the frequently methylated genes among patients with ovarian cancer. Therefore, our study aimed to better determine the prognostic and cancer characteristics effects of RASSF1A, BRCA1, APC, and p16 promoter methylation in ovarian cancer patients. Methods: Databases such as PubMed, Web of Science, EMBASE, CNKI, and WanFang were searched for published studies up to March 4, 2024. The outcomes are shown as OR and HR with their 95% CIs. Then, the random or fixed-effect model was performed to evaluate the effect sizes. Results: Finally, 27 articles were included in this meta-analysis. No significant relationships were observed between RASSF1A, BRCA1, and APC promoter methylation and the clinical prognostic (including overall survival and progression-free survival) and cancer characteristics (including ascites, lymph node metastasis, and pelvic peritoneal metastasis) in ovarian cancer. p16 promoter methylation was significantly related to poor progression-free survival (PFS) (HR = 1.52, 95% CI = 1.14–2.04) and overall survival (OS) (HR = 1.39, 95% CI = 1.06, to 1.83) in univariate and poor PFS in multivariate Cox regression models (HR = 1.42, 95% CI = 1.05–1.92). Besides, our results indicated that the clinical stage was associated with inferior OS while there was no significant association between tumor grade and OS. Conclusion: RASSF1A, BRCA1, and APC promoter methylation were not significantly associated with clinical prognostic and cancer characteristics. p16 may be a useful biomarker for predicting PFS in ovarian cancer. Furthermore, the clinical stage was significantly associated with OS. In further research, more prospective and multicenter validation studies remain needed. [ABSTRACT FROM AUTHOR]

The Caucasian pine vole Microtus daghestanicus was characterized by high karyotypic and molecular genetic variability. However, in the eastern part of the Greater Caucasus, the populations of this species were poorly studied. To reveal the genetic characteristics of these populations and their phylogenetic relationships with other conspecific populations, a sample of Caucasian pine voles from the south of the Chechen Republic (Daikhokh Mount) was analyzed. Immunocytochemical analysis of the synaptonemal complexes at meiotic prophase I showed the belonging of the studied population to the most widespread 54-chromosomal form of M. daghestanicus. Analysis of the complete sequence of the mitochondrial cytochrome b gene showed that on the phylogenetic tree, specimens from the Chechen Republic and the previously studied Caucasian pine vole from North Georgia grouped into one compact cluster. It indicates that they belong to a distinct genetic form. Within the studied sample from the Chechen Republic, variation of the BRCA1 and XIST nuclear genes was revealed that probably reflects complex history of this population associated with alternating events of its isolation from neighboring populations and restoration of contacts between them. [ABSTRACT FROM AUTHOR]

Background/Objectives: In 2020, ovarian cancer ranked fourth in global incidence among gynecological cancers and remains the deadliest cancer affecting women's health. Survival rates are significantly higher when the disease is detected at early stages; however, the lack of effective early detection methods underscores the importance of identifying risk factors in order to implement preventive strategies. The objective of this work is to provide an overview of the risk factors of ovarian cancer in South America, emphasizing those linked to social determinants, genetic components, and comorbidities. Methods: A literature search was performed using PubMed and Google Scholar. MeSH descriptors and keywords, such as "BRCA1 genes," "BRCA2 genes", "Latin America", and "ovarian neoplasms" were used, along with terms related to socioeconomic and health factors. Inclusion criteria focused on original studies published in the last five years involving South American women. Results: Studies were identified from Argentina, Brazil, Chile, Colombia, Ecuador, and Peru. These studies addressed genetic factors, health status at diagnosis, and sociodemographic factors, revealing important data gaps, particularly on contraception and hormone replacement therapy. The prevalence of BRCA1 and BRCA2 mutations in South America is estimated to be 15–20% among women with inherited risk factors. Social, demographic and economic factors vary by country, although commonalities include a higher prevalence among women over 50 years of age, those with limited education, and those who face barriers to accessing health care. Conclusions: Although the literature does not conclusively establish a direct link between obesity and/or diabetes and the development of ovarian cancer, the indirect association highlights the need for further clinical studies. A general research gap related to risk factors of ovarian cancer could be observed in the South American region. [ABSTRACT FROM AUTHOR]

Despite recent advances in the treatment of metastatic prostate cancer, progression to a castration-resistant state remains inevitable for most and prognosis is limited. Genetic testing for homologous recombination repair pathway alterations is recommended for all patients with advanced prostate cancer given that a mutation is present in up to 25% of cases. Poly(ADP-ribose) polymerase (PARPis) are now approved for use in patients with metastatic castration-resistant prostate cancer who have progressed on an androgen receptor pathway inhibitor (ARPI) and harbour a germline or somatic homologous recombination repair mutation. Preclinical data support a synergistic effect with an ARPI and PARPi, and various ARPI-PARPi combinations have therefore been explored in phase III clinical trials. Despite heterogeneous findings, a clear hierarchy of benefit is evident, with patients harbouring a BRCA mutation deriving the greatest magnitude of benefit, followed by any homologous recombination repair mutation. The benefit in homologous recombination repair-proficient cohort is less clear, and questions remain about whether ARPI-PARPi combination therapy should be offered to patients without a homologous recombination repair mutation. With ARPIs now considered standard-of-care for metastatic hormone-sensitive prostate cancer, ARPI-PARPi combination therapy is currently being explored earlier in the treatment paradigm. The purpose of this review is to discuss the rationale behind ARPI-PARPi combination therapy, summarise the results of key clinical trials, and discuss clinical considerations and future perspectives. [ABSTRACT FROM AUTHOR]

BRCA1 and 2 play important roles in double-strand break repair, replication fork protection, and prevention and resolution of single-stranded DNA gaps. These functions are closely intertwined and probably not mutually exclusive. BRCA1 and 2 play multiple roles in gap prevention and resolution, although their mechanism of action is not fully understood. The role of BRCA1/2 in ssDNA gap suppression is involved in their tumour-suppressive functions and results in chemosensitivity if inhibited, although it is unclear whether this is a direct or indirect effect. The tumour-suppressive roles of BRCA1 and 2 have been attributed to three seemingly distinct functions – homologous recombination, replication fork protection, and single-stranded (ss)DNA gap suppression – and their relative importance is under debate. In this review, we examine the origin and resolution of ssDNA gaps and discuss the recent advances in understanding the role of BRCA1/2 in gap suppression. There are ample data showing that gap accumulation in BRCA1/2-deficient cells is linked to genomic instability and chemosensitivity. However, it remains unclear whether there is a causative role and the function of BRCA1/2 in gap suppression cannot unambiguously be dissected from their other functions. We therefore conclude that the three functions of BRCA1 and 2 are closely intertwined and not mutually exclusive. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer in females. Although rare in the younger population, individuals with a susceptible genetic background are at higher risk of breast cancer. A study was conducted on 63 Finnish breast cancer patients without any BRCA1/2 variants who had an onset of breast cancer at age 40 or younger. These patients were sequenced, and variants in DNA repair genes were identified. These variants were then prioritized based on their allele frequency in the population and pathogenicity prediction scores to identify potential new risk variants. Seventy-two deleterious variants were found, including eight novel variants. For the novel variants, protein structure modeling was conducted, and all deleterious variants were validated in another Finnish BRCA1/2-negative breast cancer population. Background: Breast cancer is the most common malignancy, with a mean age of onset of approximately 60 years. Only a minority of breast cancer patients present with an early onset at or before 40 years of age. An exceptionally young age at diagnosis hints at a possible genetic etiology. Currently, known pathogenic genetic variants only partially explain the disease burden of younger patients. Thus, new knowledge is warranted regarding additional risk variants. In this study, we analyzed DNA repair genes to identify additional variants to shed light on the etiology of early-onset breast cancer. Methods: Germline whole-exome sequencing was conducted in a cohort of 63 patients diagnosed with breast cancer at or before 40 years of age (median 33, mean 33.02, range 23–40 years) with no known pathogenic variants in BRCA genes. After filtering, all detected rare variants were sorted by pathogenicity prediction scores (CADD score and REVEL) to identify the most damaging genetic changes. The remaining variants were then validated by comparison to a validation cohort of 121 breast cancer patients with no preselected age at cancer diagnosis (mean 51.4 years, range 28–80 years). Analysis of novel exonic variants was based on protein structure modeling. Results: Five novel, deleterious variants in the genes WRN, RNF8, TOP3A, ERCC2, and TREX2 were found in addition to a splice acceptor variant in RNF4 and two frameshift variants in EXO1 and POLE genes, respectively. There were also multiple previously reported putative risk variants in other DNA repair genes. Conclusions: Taken together, whole-exome sequencing yielded 72 deleterious variants, including 8 novel variants that may play a pivotal role in the development of early-onset breast cancer. Although more studies are warranted, we demonstrate that young breast cancer patients tend to carry multiple deleterious variants in one or more DNA repair genes. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the most frequent malignancies in women. The treatment landscape underwent significant changes as new agents were introduced in ovarian cancer management over the last decade. We present two cases of long responses to Olaparib in BRCA (BReast CAncer gene) mutant ovarian cancer patients. The first case belongs to a 42-year-old female diagnosed with advanced ovarian carcinoma with a rare germinal mutation (BRCA1 c.68_69delAG, commonly found in descendants of Ashkenazi Jewish populations, but also Arabic and Asian ones) and a significant family history of ovarian and breast cancers. After poorly tolerated neoadjuvant chemotherapy, the patient underwent total hysterectomy, bilateral adnexectomy, and intraperitoneal hyperthermic chemotherapy. After eight months, the disease progressed, and first-line platinum chemotherapy was administered. Although not well-tolerated (grade 3 anemia, allergic reactions), chemotherapy resulted in a partial response, and given the patient's characteristics, maintenance with Olaparib was recommended. Treatment is ongoing (total current duration 69 months) and tolerated well (grade 1 side effects). This case illustrates the long-term benefits that novel therapies like Olaparib may offer in patients with platinum-sensitive relapsed ovarian cancer harboring a rare BRCA mutation. The second case highlights a 55-year-old postmenopausal woman diagnosed with ovarian cancer, FIGO stage IVA. Initial treatment included six cycles of chemotherapy, which led to a partial response, followed by interval debulking surgery and another four cycles of chemotherapy. Subsequent Olaparib maintenance therapy post BRCA1 mutation identification contributed to a significant progression-free survival of 65 months until disease recurrence and secondary cytoreductive surgery, showcasing the effectiveness of PARP inhibitors in personalized oncology treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Objectives: To report the long‐term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi‐national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2). Subjects and Methods: Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36‐item Short‐Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge. Results: A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non‐carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer‐specific distress or poor health‐related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate‐specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA‐specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. Conclusion: This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA‐based screening programme does not have an adverse impact on psychosocial health or health‐related quality of life in these higher‐risk individuals. These results are important as more PrCa screening is targeted to higher‐risk groups. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether 6 months of preoperative apalutamide for intermediate‐risk prostate cancer (IRPCa) reduces the aggregate postoperative radiotherapy risk and to evaluate associations of molecular perturbations with clinical outcomes in this study cohort. Patients and Methods: Between May 2018 and February 2020, eligible patients with IRPCa (Gleason 3 + 4 or 4 + 3 and clinical T2b‐c or prostate‐specific antigen level of 10–20 ng/mL) were treated with apalutamide 240 mg/day for 6 months followed by radical prostatectomy (RP) in this single‐arm, phase II trial. The primary endpoint was presence of any adverse pathological feature at risk of pelvic radiation (pathological T stage after neoadjuvant therapy [yp]T3 or ypN1 or positive surgical margins). Translational studies, including germline and somatic DNA alterations and RNA and protein expression, were performed on post‐apalutamide RP specimens, and assessed for associations with clinical outcomes. Results: A total of 40 patients underwent a RP, and only one patient discontinued apalutamide prior to 6 months. In all, 40% had adverse pathological features at time of RP, and the 3‐year biochemical recurrence (BCR) rate was 15%, with 27.5% being not evaluable. Genomic alterations frequently seen in metastatic PCas, such as androgen receptor (AR), tumour protein p53 (TP53), phosphatase and tensin homologue (PTEN), or BReast CAncer associated gene (BRCA1/2) were underrepresented in this localised cohort. Adverse pathological features and BCR at 3‐years were associated with increased expression of select cell cycle (e.g., E2F targets: adjusted P value [Padj] < 0.001, normalised enrichment score [NES] 2.47) and oxidative phosphorylation (Padj < 0.001, NES 1.62) pathways. Conclusions: Preoperative apalutamide did not reduce the aggregate postoperative radiation risk to the pre‐specified threshold in unselected men with IRPCa. However, transcriptomic analysis identified key dysregulated pathways in tumours associated with adverse pathological outcomes and BCR, which warrant future study. Further investigation of preoperative therapy is underway for men with high‐risk PCa. [ABSTRACT FROM AUTHOR]

The use of natural substances in cancer treatment is gaining popularity due to their potentially lower side effects compared to radiation or chemotherapy. The development of these substances for the treatment of cancer has been successful. New technologies now incorporate nanoformulations for nanomedicines that are intended to increase the anticancer potential of drugs synthesized from phytocompounds. Essential oil from Catharanthus roseus plant was extracted and incorporated into IA-NE and assess anticancer activity of synthesized formulation against breast cancer. The 9, 10-dimethylbenz[a] anthracene (DMBA) induced rat mammary tumor model was used to evaluate anticancer properties of biosynthesized nanoemulsion Nanoemulsions was examined for in vitro cytotoxicity activity, anti-cancer effects, and physicochemical characteristics. Study findings demonstrated that incensole acetate mediated nanoemulsion may successfully improve tumor parameters, oxidative stress enzyme levels and over expressed WWP1 level in DMBA induced rats. The present investigations indicate the effect of nanoemulsion to reduce expression level of WWP1 gene significantly in breast cancer induced model. Therefore, this nanoformulation is considered a key therapeutic agent for future cancer treatment, pending extensive molecular studies. [Display omitted] • Formulation and characterization of nanoformulation was performed by interpreting its UV, SEM, Zeta size and PDI. • Investigate the effects of synthesized nanoemulsion on DMBA tumor parameters. • Analysis of oxidative stress markers in cancer induced animals as treated with nanoemulsion. • Optimized nanoemulsions had a significant cytotoxicity against MBA-MB-231 cancer cell lines. • Investigation of WWP1 gene expression in cancer induced animals as treated with nanoemulsion. [ABSTRACT FROM AUTHOR]

BRCA1/2 previvors – individuals who have a genetic mutation that increases their lifetime risk of developing breast or ovarian cancer – have unique information needs. Previvors can experience distress and uncertainty when these needs are not met, which can have negative consequences on their physical and psychological health. Previous research suggests meeting previvors' information needs is one way to combat these potential harmful effects. However, limited past research has examined previvors' perceptions of the helpfulness of information. Therefore, through surveying 101 previvors, this study explored previvors' perceptions of the (un)helpfulness of information, what (lack of) barriers previvors face to finding desired information, and the information sources they utilized. A thematic analysis revealed that previvors generally viewed information as helpful (through empowerment, coping, camaraderie, and action) but not always (evident in information overload). Previvors also reported several barriers (such as "the healthcare system in general", exclusivity, and uncertainty), while others reported a lack of resistance to finding desired information. Additionally, frequencies were calculated to find that various healthcare providers, support groups, and friends and family were common information sources. Taken together, these results offer a psychosocial model for understanding the previvor information journey, displaying how the themes are interconnected and unique for each previvor. [ABSTRACT FROM AUTHOR]

Background: There is no consensus regarding the specific genes included in the homologous recombination repair (HRR) gene panel for identifying the HRR deficiency (HRD) status and predicting the prognosis of epithelial ovarian cancer (EOC) patients. Objective: We aimed to explore a 15-gene panel involving the HRR pathway as a predictive prognostic indicator in Chinese patients newly diagnosed with EOC. Patients and Methods: We reviewed the previously published reports about different HRR gene panels and prespecified the 15-gene panel. The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centers were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and progression-free survival (PFS) with 15-gene panel HRR mutations (HRRm) status was assessed. Results: 43.2% (133/308) of patients were determined to carry 144 deleterious HRRm, among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. The hazard ratio (HR) (95% confidence interval, CI) for PFS (HRRm v HRR wild type, HRRwt) using the 15-gene panel HRRm was 0.42 (0.28–0.64) at all stages and 0.42 (0.27–0.65) at stages IIIC–IV. However, a prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. For the subgroups of patients not using PARPis, the HR (95% CI) was 0.41 (0.24–0.68) at stages IIIC–IV. Conclusions: This study provides evidence that 15-gene panel HRRm can predict the prognosis of EOC, of these only the BRCA1/2 mutations, not non-BRCA HRRm, contribute to prognosis prediction. Among patients without PARPis, the HRRm group presented a better PFS. This is the first study of this kind in the Chinese population. [ABSTRACT FROM AUTHOR]

Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery. • In young BRCA carriers, hormone receptor status did not appear to be a strong positive prognostic factor. • Patients with luminal A-like disease seem to have the worst DFS compared to all the other subtypes. • Treatment, surveillance, and prevention strategies based on disease biology are recommended in young BRCA carriers. [ABSTRACT FROM AUTHOR]

Background: Bladder carcinoma (BLCA) is characterized by high morbidity, mortality, and treatment costs. Breast cancer gene 1 (BRCA1), a tumor suppressor gene, inhibits the development of malignant tumors. However, research on the significance of BRCA1 in BLCA is limited. This study aims to explore the importance of BRCA1 in BLCA using bioinformatic methods and immunohistochemistry. Methods: Gene expression, clinical, and survival data were collected from the TCGA databases through the UCSC Xena platform (http://xena.ucsc.edu/). The TPM data from the TCGA and GETEx databases were integrated using the GEPIA database (http://GEPIA.cancer-pku.cn). The study then explored the differential expression, survival prognosis, functional enrichment, and immune cell infiltration analyses of BRCA1 in BLCA. A PPI network of BRCA1 was constructed using the STRING database, and a BRCA1-associated gene-gene interaction network was generated using the GeneMANIA database. Immunohistochemistry (IHC) assays were performed to verify the expression levels of BRCA1 in bladder tumour tissues and adjacent normal tissues. Results: BRCA1 is associated with BLCA. Differential analysis indicated that BRCA1 acts as a risk factor for BLCA but does not show significant expression differences across genders, stages, tumor stages, lymph node stages, or metastasis stages. Additionally, staging was based on the eighth edition of the American Joint Committee on Cancer (AJCC) for BLCA. Co-expression network and Gene Set Enrichment Analysis (GESA) confirmed that BRCA1 is involved in various BLCA pathways. Furthermore, BRCA1 expression was also linked to immune cell infiltration. However, survival prognosis analysis revealed no significant correlation between the prognosis of BLCA and BRCA1. Conclusion: We demonstrated that BRCA1 is a prospective predicted and immunological biomarker in BLCA, offering new avenues for potential therapies. [ABSTRACT FROM AUTHOR]

Background: Genetic testing for persons with a heightened likelihood of harboring a germline mutation permits early identification and appropriate management. This study aimed to identify the proportion of breast cancer (BC) patients who were offered genetic testing and the prevalence of BRCA mutations among them. Additionally, we assessed the demographic and clinical features of BC patients in the Eastern Region of Saudi Arabia. Materials and Methods: Data from 2535 patients with BC were retrieved from the registry between 2017 and 2021. The data were analyzed and presented using univariate and bivariate statistics. Odds ratios and 95% confidence intervals using logistic regression analysis were computed to identify the predictors of BRCA testing. Results: Patients with BC ranged in age from 18 to 103 years, and the mean age was 49.60 ± 12.14 years. BC was detected in men in 29 (1.1%) cases. Among diagnosed patients with BC, a total of 96 (3.7%) patients underwent testing for BRCA gene mutations. Of them, 36 (37.5%) patients had a BRCA gene mutation. The likelihood of undergoing BRCA testing was higher for those who were diagnosed with the condition before the age of 50, patients who were referred from private institutions, and patients with a history of previously diagnosed cancer. The likelihood of conducting BRCA testing was significantly lower among those with distant metastases. Conclusion: The proportion of BRCA testing among BC patients was found to be relatively low. The development of a cost-effective, locally developed risk assessment tool that incorporates genetic counseling and testing for those with a familial predisposition to BC is imperative. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common cancer in women, and therapeutic strategies for it are based on the molecular subtypes of luminal BC, HER2 BC, and triple-negative BC (TNBC) because each subtype harbors different unique genetic aberrations. Recently, features of the tumor microenvironment (TME), especially cancer-associated fibroblasts (CAFs), have been demonstrated to play a critical role in BC progression, and we would like to understand the molecular features of BC CAFs for novel therapeutic strategies. In a recent study, 115 CAF-associated genes (CAFGs) were identified in a public database of microdissection and microarray data (GSE35602) from 13 colorectal cancer (CRC) tumors. Using a public database (GSE10797) of 28 BC tumors, a similar analysis was performed. In BC, 59 genes from the 115 CAFGs identified in CRC (CRC CAFGs) were also closely associated with a CAFs marker, SPARC (R = 0.6 or beyond), and POSTN was of particular interest as one of the BC CAFGs with the highest expression levels and a close association with SPARC expression (R = 0.94) in the cancer stroma of BC tumors. In BC stroma, POSTN was followed in expression levels by DKK3, MMP2, PDPN, and ACTA2. Unexpectedly, FAP and VIM were not as highly associated with SPARC expression in the cancer stroma of BC tumors and exhibited low expression. These findings suggested that ACTA2 might be the most relevant conventional CAFs marker in BC, and ACTA2 was actually correlated in expression with many CRC CAFGs, such as SPARC. Surprisingly, the SE ratio values of the BC CAFGs were much lower (average SE = 3.8) than those of the CRC CAFGs (SE = 10 or beyond). We summarized the current understanding of BC CAFs from the literature. Finally, in triple-negative BC (TNBC) (n = 5), SPARC expression uniquely showed a close association with COL11A1 and TAGLN expression, representing a myofibroblast (myCAFs) marker in the cancer stroma of the BC tumors, suggesting that myCAFs may be molecularly characterized by TNBC in contrast to other BC phenotypes. In summary, CAFs could have unique molecular characteristics in BC, and such TME uniqueness could be therapeutically targeted in BC. [ABSTRACT FROM AUTHOR]

Introduction: Niraparib first-line maintenance (1LM) therapy has demonstrated clinical benefit for patients with ovarian cancer (OC) in clinical trial and real-world settings, but data on factors associated with real-world patient outcomes remain limited. This analysis identified patient characteristics associated with time to next treatment (TTNT), a proxy for real-world progression-free survival, in patients with OC treated with 1LM niraparib monotherapy. Methods: This retrospective observational study used a USA nationwide electronic health record-derived deidentified database and included adult patients diagnosed with OC who initiated 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Patients were followed until the earliest occurrence of last clinical activity, death, or end of study period. TTNT was measured from 1LM niraparib initiation to the start of second-line treatment or death. Cox proportional hazards models assessed univariable and multivariable associations between baseline characteristics and TTNT. Results: Of 7872 patients diagnosed with OC, 526 met the eligibility criteria and were included in this analysis. Median (IQR) duration of follow-up was 14.1 (7.4–23.6) months. In univariable analyses, age, BRCA/homologous recombination deficiency (HRD) status, socioeconomic status, stage at initial diagnosis, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT and were introduced into the multivariable model with other clinically relevant variables. In the multivariable analysis, BRCA/HRD status, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT after covariate adjustment. Conversely, age, Eastern Cooperative Oncology Group performance status, disease stage, niraparib starting dose status, and first-line bevacizumab use were not associated with observed TTNT. Conclusion: This real-world, retrospective, observational analysis offers valuable insights on prognostic factors associated with TTNT in patients with OC treated with 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Future studies are needed to examine how additional patient characteristics associated with clinical outcomes may guide treatment decisions and improve outcomes. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is the most prevalent cancer and the leading cause of cancer-related deaths in women globally. Cysteine protease cathepsin-B has been implicated in various human malignancies and is involved in malignancy progression and metastasis. This study aimed to evaluate the circulating levels of cathepsin-B, interleukin-6 (IL-6), and CA15-3, a cancer antigen, as biomarkers for tumors in women with both localized and metastatic BC. The study employed a case-control design, enrolling 108 participants categorized into three groups: healthy individuals, those with localized BC, and those with metastatic BC. The relative mRNA expression of cathepsin-B in blood samples was assessed using qRT-PCR. Additionally, serum levels of IL-6 and CA15-3 were quantified using ELISA. Results: The relative mRNA expression of cathepsin-B, IL-6 levels, and CA15-3 levels were significantly higher in metastatic BC cases than in localized BC cases and the control group (p-value < 0.001). A statistically significant positive correlation was also found between cathepsin-B and both IL-6 and CA15-3 (r = 0.905, r = 0.667, and p < 0.001), respectively. Conclusions: The findings indicate a strong correlation between the interaction of the proteolytic enzyme cathepsin-B and IL-6 with the unfavorable prognosis of BC. This relationship may serve as a potential indicator and a promising target for therapy in BC treatment. [ABSTRACT FROM AUTHOR]

Breast Cancer Type 1 Susceptibility Protein (BRCA1) is a tumor-suppressor protein that regulates various cellular pathways, including those that are essential for preserving genome stability. One essential mechanism involves a BRCA1-A complex that is recruited to double-strand breaks (DSBs) by RAP80 before initiating DNA damage repair (DDR). How RAP80 itself is recruited to DNA damage sites, however, is unclear. Here, we demonstrate an intrinsic correlation between a methyltransferase DOT1L-mediated RAP80 methylation and BRCA1-A complex chromatin recruitment that occurs during cancer cell radiotherapy resistance. Mechanistically, DOT1L is quickly recruited onto chromatin and methylates RAP80 at multiple lysines in response to DNA damage. Methylated RAP80 is then indispensable for binding to ubiquitinated H2A and subsequently triggering BRCA1-A complex recruitment onto DSBs. Importantly, DOT1L-catalyzed RAP80 methylation and recruitment of BRCA1 have clinical relevance, as inhibition of DOT1L or RAP80 methylation seems to enhance the radiosensitivity of cancer cells both in vivo and in vitro. These data reveal a crucial role for DOT1L in DDR through initiating recruitment of RAP80 and BRCA1 onto chromatin and underscore a therapeutic strategy based on targeting DOT1L to overcome tumor radiotherapy resistance. [ABSTRACT FROM AUTHOR]

Background: Fear of cancer recurrence (FCR) affects virtually all patients who have been treated for cancer, to varying degrees. Breast cancer survivors who carry a BRCA1 or BRCA2 gene mutation are at high risk of cancer recurrence. No study has yet assessed FCR specifically in this population. Objectives: This cross-sectional study, conducted in women who were treated for breast cancer and carrying a BRCA1/2 mutation, aimed to: (1) assess the mean level of FCR and estimate the proportion of patients with clinical levels of FCR; (2) examine the relationships between FCR and selected psychological variables (e.g., avoidance, intolerance to uncertainty) and quality of life; (3) explore whether FCR levels vary as a function of the past preventive treatment received; and (4) to assess the associations between FCR and the presence of decisional conflict or regret regarding the various preventive options. Method: Participants were recruited through an e-mail sent to an oncogenetic network mailing list (Réseau ROSE). Participants were asked to complete a battery of questionnaires online assessing FCR and other psychological and quality of life variables. Results: A total of 89 women completed the survey. Most participants had undergone a preventive mastectomy (62.9%) and a preventive salpingo-oophorectomy (75.3%) at the time of the study. The mean Fear of Cancer Recurrence Inventory-severity score was 16.8, which exceeds the clinical cut-off score of 13, and 70.8% of the participants showed a clinical level of FCR. FCR was significantly associated with higher levels of anxiety and depression, and higher avoidance and intolerance of uncertainty, but not with quality of life. No significant difference was observed on the total FCR score between women who had received preventive surgery (mastectomy and/or salpingo-oophorectomy) and those considering it, and those not considering it. The association was significant between higher FRC scores and greater decisional conflicts and regrets about choosing to undergo preventive surgery. Conclusion: These data suggest that FCR is a significant problem for breast cancer survivors carrying a BRCA1/2 genetic mutation, even after undergoing a prophylactic surgery. This highlights the importance of providing these women with specific psychological intervention focusing on FCR. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a prevalent public health concern affecting numerous women globally and is associated with palmitoylation, a post-translational protein modification. Despite increasing focus on palmitoylation, its specific implications for breast cancer prognosis remain unclear. The work aimed to identify prognostic factors linked to palmitoylation in breast cancer and assess its effectiveness in predicting responses to chemotherapy and immunotherapy. Methods: We utilized the "limma" package to analyze the differential expression of palmitoylation-related genes between breast cancer and normal tissues. Hub genes were identified using the "WGCNA" package. Using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis, we identified a prognostic feature associated with palmitoylation and developed a prognostic nomogram with the "regplot" package. The predictive values of the model for chemotherapy and immunotherapy responses were assessed using immunophenoscore (IPS) and the "pRophetic" package. Results: We identified 211 differentially expressed genes related to palmitoylation, among which 44 demonstrated prognostic potential. Subsequently, a predictive model comprising eleven palmitoylation-related genes was developed. Patients were classified into high-risk and low-risk groups based on the median risk score. The findings revealed that individuals in the high-risk group exhibited lower survival rates, while those in the low-risk group showed increased immune cell infiltration and improved responses to chemotherapy and immunotherapy. Moreover, the BC-Palmitoylation Tool website was established. Conclusion: This study developed the first machine learning-based predictive model for palmitoylation-related genes and created a corresponding website, providing clinicians with a valuable tool to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Ganciclovir (GCV) is a clinically important drug as it is used to treat viral infections. GCV is incorporated into the DNA during replication, where it interferes with subsequent replication on GCV‐incorporated templates. However, the effects of GCV on the host genome and the mechanisms underlying cellular tolerance to GCV remain unclear. In this study, we explored these mechanisms using a collection of mutant DT40 cells. We identified RAD17/−, BRCA1−/−, and RAD18−/− cells as highly GCV‐sensitive. RAD17, a component of the alternative checkpoint‐clamp loader RAD17‐RFC, was required for the activation of the intra‐S checkpoint following GCV treatment. BRCA1, a critical factor for promoting homologous recombination (HR), was required for suppressing DNA double‐strand breaks (DSBs). Moreover, RAD18, an E3‐ligase involved in DNA repair, was critical in suppressing the aberrant ligation of broken chromosomes caused by GCV. We found that BRCA1 suppresses DSBs through HR‐mediated repair and template switching (TS)‐mediated damage bypass. Moreover, the strong GCV sensitivity of BRCA1−/− cells was rescued by the loss of 53BP1, despite the only partial restoration in the sister chromatid exchange events which are hallmarks of HR. These results indicate that BRCA1 promotes cellular tolerance to GCV through two mechanisms, TS and HR‐mediated repair. [ABSTRACT FROM AUTHOR]

Purpose: This study seeks to contribute real-world data on the prevalence of BRCA1/2 and HRR gene mutations in prostate cancer. Methods: We compiled sequencing data of 197 cases of primary and metastatic prostate cancer, in which HRR mutation analysis was performed upon clinical request within the last 5 years. All cases were analyzed using a targeted NGS BRCAness multigene panel, including 8 HRR genes (ATM, BRCA1, BRCA2, CDK12, CHEK2, FANCA, HDAC2, PALB2). Results: Our findings reveal a prevalence of potentially targetable mutations based on FDA criteria of 20.8%, which is comparable to the literature. However, the frequency of targetable BRCA2 mutations within our cohort was lower than reported for mCRPC and ATM and CHEK2 mutations were more prevalent instead. Thus, while 20.8% (n = 38) of the cases meet the criteria for olaparib treatment per FDA approval, only 4.9% (n = 9) align with the eligibility criteria according to the EMA approval. Conclusion: This study offers valuable real-world insights into the landscape of BRCA1/2 and HRR gene mutations and the practical clinical management of HRR gene testing in prostate cancer, contributing to a better understanding of patient eligibility for PARPi treatment. [ABSTRACT FROM AUTHOR]

Poly (ADP‐ribose) polymerase 1 is a versatile enzyme that is deeply involved in diverse cellular processes. It exerts influence on pivotal activities such as DNA repair, transcriptional regulation, and cell death. PARP1 is crucial due to its susceptibility to posttranslational modifications, each of which has distinct roles in shaping its functionality and interactions with other proteins. Among these modifications, the addition of ADP‐ribose polymerase 1 and the addition of an acetyl group to lysine residues enhance PARP1 engagement in DNA repair, while ubiquitination and cleavage are involved in the degradation of PARP1. PARP1 modification has been exploited in cancer treatment, particularly in the context of breast and ovarian cancers marked by BRCA1 and BRCA2 mutations. However, resistance to PARP1 inhibitors and selective posttranslational modifications, which confer cellular functions remain elusive. The present review endeavors to detail the extent of PARP1 modifications, shedding light on their profound implications at the cellular remains a challenge, which often drives treatment failure. The effectiveness of PARP1 inhibitors relies on specific level. This trial is registered with NCT04550104, NCT06120491, NCT05367440, NCT05797168, NCT04644068, NCT05573724, NCT05489211, NCT05938270, and NCT02264678. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer (BRCA) is a significant cause of cancer-associated mortality across the globe. Current therapeutic approaches face challenges such as drug resistance and metastasis. Immune signaling is triggered by chromosomal instability (CIN) generates misplaced DNA structures that activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGASSTING) pathway, triggering. Studies have linked STING activation to BRCA treatment. Methods: The bulk RNA-seq data for patients with BRCA were collected from the TCGA-BRCA cohort, GSE20685, and GSE96058 cohorts. STING pathway-related genes (SRGs) were obtained from the Reactome database. Differentially expressed genes were analyzed using the limma package. Immune cell infiltration was analyzed using the IOBR package. Gene Ontology biological processes, Kyoto Encyclopedia of Genes and Genomes pathways, and cancer hallmark pathways were analyzed using the MSigDB database. Prognostic models were prepared using the least absolute shrinkage and selection operator and multiple-factor Cox regression analysis. Single-cell analysis was performed using the Seurat and SCP pipeline. Results: The expression patterns and clinical relevance of SRGs were analyzed in patients with BRCA. Transcriptional differences in the SRGs were observed between normal and tumorous tissues, with global down-regulated STING1 and up-regulated TBK1 in BRCA tissue. Tumor tissues were classified through consensus clustering analysis into two distinct groups, with differences in clinical characteristics and immune infiltration. A prognostic model related to the differences in STING pathway activity--high prognostic stratification potency--was developed and validated. Correlation analysis revealed suppressed overall immune activation in patients with BRCA having higher risk scores. Gemcitabine had a more favorable outcome in the low-risk group. The activity of the prognostic model at the single-cell level was confirmed through single-cell analysis, particularly in CD8 T cells and intratumor natural killer cells. Conclusion: A STING pathway-related prognostic model developed and validated and the model could accurately predict BRCA patient outcomes. These findings have important implications for the personalized treatment and management of patients with BRCA. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) and breast cancer pose significant risks to human health. The reasons behind the concurrent occurrence of AF and breast cancer remain unclear, leading to complex treatment approaches. Mendelian Randomization (MR) analyses aim to offer genetic evidence supporting the causation of AF and breast cancer and to investigate common druggable genes associated with both conditions. Methods: We used two-samples of MR to sequentially explore the causal relationship between atrial fibrillation and breast cancer, and between atrial fibrillation and breast cancer therapeutic drugs, and verified the stability of the results through colocalization analysis. We utilized the Connectivity map database to infer the direction of drug effects on disease. Finally, we explored druggable genes that play a role in AF and breast cancer and performed a Phenome-wide MR analysis to analyze the potential side effects of drug targets. Results: We found 15 breast cancer therapeutic drugs that significantly support a causal association between AF and breast cancer through expression in blood and/or atrial appendage tissue. Among these, activation of ANXA5 by Docetaxel, inhibition of EIF5A by Fulvestrant, and inhibition of GNA12 by Tamoxifen increased the risk of AF, while inhibition of ANXA5 by Gemcitabine and Vinorebine and inhibition of PCGF6 by Paclitaxel reduced the risk of AF. Inhibition of MSH6 and SF3B1 by Cyclophosphamide, as well as inhibition of SMAD4 and PSMD2 and activation of ASAH1 and MLST8 by Doxorubicin can have bidirectional effects on AF occurrence. XBP1 can be used as a common druggable gene for AF and breast cancer, and there are no potential side effects of treatment against this target. Conclusion: This study did not find a direct disease causality between AF and breast cancer but identified 40 target genes for 15 breast cancer therapeutic drugs associated with AF, clarified the direction of action of 8 breast cancer therapeutic drugs on AF, and finally identified one common druggable target for AF and breast cancer. [ABSTRACT FROM AUTHOR]

DSS1, essential for BRCA2-RAD51 dependent homologous recombination (HR), associates with the helical domain (HD) and OB fold 1 (OB1) of the BRCA2 DSS1/DNA-binding domain (DBD) which is frequently targeted by cancer-associated pathogenic variants. Herein, we reveal robust ss/dsDNA binding abilities in HD-OB1 subdomains and find that DSS1 shuts down HD-OB1's DNA binding to enable ssDNA targeting of the BRCA2-RAD51 complex. We show that C-terminal helix mutations of DSS1, including the cancer-associated R57Q mutation, disrupt this DSS1 regulation and permit dsDNA binding of HD-OB1/BRCA2-DBD. Importantly, these DSS1 mutations impair BRCA2/RAD51 ssDNA loading and focus formation and cause decreased HR efficiency, destabilization of stalled forks and R-loop accumulation, and hypersensitize cells to DNA-damaging agents. We propose that DSS1 restrains the intrinsic dsDNA binding of BRCA2-DBD to ensure BRCA2/RAD51 targeting to ssDNA, thereby promoting optimal execution of HR, and potentially replication fork protection and R-loop suppression. DSS1 is crucial for BRCA2 dependent genome repair. Here, the authors reveal how DSS1 restricts the dsDNA binding ability of BRCA2 to ensure BRCA2/RAD51 loading on ssDNA. Mutations in DSS1 disrupt this regulation, leading to impaired DNA repair, replication fork protection and R-loop suppression. [ABSTRACT FROM AUTHOR]

Background: Breast cancer has emerged as the foremost cause of female mortality worldwide, with triple negative breast cancer accounting for approximately 10–15% of all breast cancer cases. The triple negative breast cancer family has obvious familial heritability, but no potential pathogenic variation was found in BRCA1/2. Case presentation: The patient was a 56-year-old woman of Han ethnicity. The clinical characteristics of this patient with breast cancer were summarized, peripheral blood of one normal female and two patients with breast cancer in this family was collected, DNA was extracted, and the potential pathogenic variation was analyzed by whole exome sequencing. The normal female and two patients with breast cancer in this family shared a maternal grandmother. The proband's right breast mass was punctured, and the biopsy showed invasive carcinoma of the right breast, grade II–III, with necrosis. No mutation was found in BRCA1/2 gene test; immunohistochemical of surgical specimens showed triple negative breast cancer. Three mutation types and 17 gene mutation sites were detected through bioinformatics prediction analysis on the basis of co-segregation of genotype and phenotype within the family and whole exome sequencing results. Combined with the Cancer Genome Atlas database comprehensive analysis, the MT1E c.G107A (p.C36Y) mutation may be a potential pathogenic site. Conclusions: Through whole exome sequencing, we identified a total of 17 potential pathogenic mutation loci, none of which have been reported thus far. Therefore, our work expanded the gene mutation spectrum of familial hereditary triple negative breast cancer, which can provide more basis for family genetic counseling. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)‐low‐expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. Methods: Women aged ≤40 years with newly diagnosed early‐stage HER2‐negative BC (HER2‐0 and HER2‐low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi‐square test and Student t‐test were used to describe variable distribution between HER2‐0 and HER2‐low. Associations with HER2‐low status were assessed with logistic regression. Kaplan–Meier method and Cox regression analysis were used to assess disease‐free survival (DFS) and overall survival. Statistical significance was considered for p ≤.05. Results: Of 3547 included patients, 32.3% had HER2‐low BC, representing 46.3% of hormone receptor–positive and 21.3% of triple‐negative (TN) tumors. HER2‐low vs. HER2‐0 BC were more often of grade 1/2 (p <.001), hormone receptor–positive (p <.001), and node‐positive (p =.003). BRCA2 PVs were more often associated with HER2‐low than BRCA1 PVs (p <.001). HER2‐low versus HER2‐0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76–0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64–0.95) and overall survival (HR, 0.65; 95% CI, 0.46–0.93) in the TN subgroup. Luminal A–like tumors in HER2‐low (p =.014) and TN and luminal A‐like in HER2‐0 (p =.019) showed the worst DFS. Conclusions: In young patients with HER2‐negative BC and germline BRCA1/2 PVs, HER2‐low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal‐like disease. HER2‐low status was associated with a modestly improved prognosis. Approximately 32% of human epidermal growth factor receptor 2 (HER2)‐negative breast cancer in an international multicenter cohort of 3547 women ≤40 years old with germline BRCA1/2 pathogenic variants was HER2‐low, and more frequently associated with hormone receptor–positive disease and BRCA2 variants than triple‐negative and BRCA1. HER2‐low status was associated with slightly better outcomes than HER2‐0, especially in triple‐negative tumors, without prognostic differences according to BRCA1 vs. BRCA2 variants, though within HER2‐low disease, luminal A–like tumors displayed worse disease‐free survival than luminal B–like and triple negative tumors. [ABSTRACT FROM AUTHOR]

Melatonin, noted for its anti-cancer properties in various malignancies, including cutaneous melanoma, shows promise in Uveal melanoma (UM) treatment. This study aimed to evaluate melatonin receptor expression in primary UM and its association with UM-related mortality and prognostic factors. Immunohistochemical analysis of 47 primary UM tissues showed low expression of melatonin receptor 1A (MTNR1A) and melatonin receptor 1B (MTNR1B), with MTNR1A significantly higher in patients who succumbed to UM. Analysis of TCGA data from 80 UM patients revealed RNA expression for MTNR1A, retinoic acid-related orphan receptor alpha (RORα), and N-ribosyldihydronicotinamide:quinone oxidoreductase (NQO2), but not MTNR1B or G protein-coupled receptor 50 (GPR50). Higher MTNR1A RNA levels were observed in patients with a BRCA1 Associated Protein 1 (BAP1) mutation, and higher NQO2 RNA levels were noted in patients with the epithelioid tumor cell type. However, Kaplan–Meier analysis did not show distinct survival probabilities based on receptor expression. This study concludes that UM clinical samples express melatonin receptors, suggesting a potential mechanism for melatonin's anti-cancer effects. Despite finding higher MTNR1A expression in patients who died of UM, no survival differences were observed. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the leading cause of cancer death among women worldwide. Women employed in shift jobs face heightened BC risk due to prolonged exposure to night shift work (NSW), classified as potentially carcinogenic by the International Agency for Research on Cancer (IARC). This risk is linked to disruptions in circadian rhythms governed by clock genes at the cellular level. However, the molecular mechanisms are unclear. This study aimed to assess clock genes as potential BC biomarkers among women exposed to long-term NSW. Clock gene expression was analysed in paired BC and normal breast tissues within Nurses' Health Studies I and II GEO datasets. Validation was performed on additional gene expression datasets from healthy night shift workers and women with varying BC susceptibility, as well as single-cell sequencing datasets. Post-transcriptional regulators of clock genes were identified through miRNA analyses. Significant alterations in clock gene expression in BC compared to normal tissues were found. BHLHE40, CIART, CLOCK, PDPK1, and TIMELESS were over-expressed, while HLF, NFIL3, NPAS3, PER1, PER3, SIM1, and TEF were under-expressed. The downregulation of PER1 and TEF and upregulation of CLOCK correlated with increased BC risk in healthy women. Also, twenty-six miRNAs, including miR-10a, miR-21, miR-107, and miR-34, were identified as potential post-transcriptional regulators influenced by NSW. In conclusion, a panel of clock genes and circadian miRNAs are suggested as BC susceptibility biomarkers among night shift workers, supporting implications for risk stratification and early detection strategies. [ABSTRACT FROM AUTHOR]

Breast cancer is the most diagnosed cancer in the world, and it is the primary cause of cancer death for women. The risk of breast cancer is increased by endogenous factors like hormones and exogenous factors like radiation exposure that causes damage to the mammary epithelial cells leading to an inflammatory response. Chronic inflammation creates a microenvironment composed of, among other factors, chemokines, and interleukins, which promote cancer. The gene expression of the interleukin 1 receptor type 1, the interleukin 1 receptor antagonist, the Interleukin 1 Receptor Accessory Protein, the interleukin 6 cytokine family signal transducer, the C-X-C motif chemokine ligand 3, the C-X-C motif chemokine ligand 5, and the C-X-C motif chemokine ligand 6 were analyzed in an estrogen and radiation experimental breast cancer model. Furthermore, the expression of these genes was correlated with immune cell infiltration, estrogen receptor expression, and their clinical relevance in breast cancer patients based on data provided by The Cancer Genome Atlas database online. Results given by the experimental breast cancer model showed that all genes related to inflammation respond to ionizing radiation alone or in combination with estrogen. On the other hand, the immune response depended on the breast cancer type and on the expression of the gene that encoded the estrogen receptor. Finally, the importance of the expression of these genes in breast cancer is such that high IL1R1 or IL1RAP is strongly related to patient survival. These findings may help to improve the understanding of the role of immune molecules in carcinogenesis and enhance therapeutic approaches. [ABSTRACT FROM AUTHOR]

Breast cancer (BC), a globally prevalent malignancy, shows significant variability in incidence across different geographical regions. In this study, we examined the expression of the tumor suppressor gene BRCA1 and the tumor marker CA15‐3 in women diagnosed with BC, focusing on different cancer grades. Our research, conducted at the Baqiyat Elah Hospital in Tehran in 2021, involved collecting blood and serum samples from BC patients. These samples underwent BRCA1 gene expression analysis and CA15‐3 tumor marker assessment. Using the AJCC grading system, we categorized BC patients into various grades. Our findings revealed that BRCA1 gene expression was present in 28.57% of patients, while 71.43% showed negative expression. Both BRCA1 expression and CA15‐3 levels significantly increased with advanced cancer stages (P < 0.001). These results suggest the potential utility of BRCA1 gene expression and CA15‐3 tumor marker assessment in BC prognosis and management, particularly concerning staging and disease progression. This study provides valuable insights into the biology of BC and the development of prognostic markers for improved patient outcomes. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) has emerged as the most common malignancy among females. The genomic profile of BC is diverse in nature and complex due to heterogeneity among various geographically different ethnic groups. The primary objective of this study was to carry out a comprehensive mutational analysis of Indian BC cases by performing whole exome sequencing. The cohort included patients with a median age of 48 years. TTN, TP53, MUC16, SYNE1, and OBSCN were the frequently altered genes found in our cohort. The PIK3CA and KLC3 genes are driver genes implicated in various cellular functions and cargo transportation through microtubules, respectively. Except for CCDC168 and PIK3CA, several gene pairings were found to be significantly linked with co-occurrence. Irrespective of their hormonal receptor status, RTK/RAS was observed with frequently altered signaling pathways. Further analysis of the mutational signature revealed that SBS13, SBS6, and SBS29 were mainly observed in our cohort. This study supplements the discovery of diagnostic biomarkers and provides new therapeutic options for the improved management of BC. [ABSTRACT FROM AUTHOR]

Objective: Rare coexistence of disease or pathology Background: Hereditary breast cancer arising in BRCA1-deficient patients is commonly diagnosed as invasive carcinoma of no special type (NST) with medullary features, while invasive lobular carcinoma (ILC) appears to be significantly under-represented in BRCA1 mutation carriers. We report a case of pleomorphic ILC arising in a 28-year-old woman harboring a germline BRCA1 c.3756_3759delGTCT p.(Ser1253Argfs*10) pathogenic variant. Case Report: A nulliparous 28-year-old woman with a family history of BRCA1 mutation presented to the symptomatic breast clinic with a several-week history of a left 80-mm breast lump. Core biopsy established a diagnosis of a poorly differentiated triple-negative breast cancer (TNBC) of pleomorphic lobular phenotype. Her clinical diagnosis was cT3, N0, M0, cStageIIB. The MDT recommended CT staging, MRI breast imaging and neoadjuvant chemotherapy (NACT). PET CT imaging showed no evidence of distant metastatic disease. The patient had a good radiological response to NACT with a FEC-T carboplatin regimen. Post-NACT imaging showed a residual cystic mass and the patient underwent a mastectomy and sentinel lymph node biopsy with plans for a delayed latissimus dorsi reconstruction following her adjuvant radiotherapy treatment. A complete pathological response was subsequently demonstrated without any evidence of metastatic disease. Conclusions: This case is the first report of pleomorphic ILC with a triple-negative receptor status and a complete pathological response in a BRCA1 mutation carrier. Our study expands the heterogeneous spectrum of TNBC and contributes to a better understanding of the molecular genetic landscape that characterizes invasive pleomorphic lobular neoplasia. [ABSTRACT FROM AUTHOR]

Background: Germline breast cancer susceptibility gene (gBRCA) mutation in patients with pancreatic cancer (PC) is not common in clinical practice. Therefore, factors that efficiently show gBRCA mutations and the real-world outcomes of olaparib maintenance therapy have not been fully established. In the present study, we clarified the indicators for the effective detection of gBRCA mutation and the efficacy and safety of olaparib as maintenance therapy. Methods: We retrospectively analyzed 84 patients with PC who underwent gBRCA testing (BRACAnalysis, Myriad Genetics, Salt Lake City, UT, USA) at our institute between January 2021 and March 2022. For each patient, clinical data were extracted from medical records. Results: The median patient age was 64 y (29–85 y), and 41 patients (48.8%) were male. The gBRCA mutations were identified in 10 (11.9%) patients; two patients had BRCA1 mutation and eight had BRCA2 mutation. All patients with gBRCA mutation had a family history of any cancer, and eight of them had a family history of Hereditary Breast and Ovarian Cancer syndrome (HBOC)-related cancer. The gBRCA mutation rate was higher for patients with PC with a family history of HBOC-related cancer compared to that in patients with PC having a family history of other cancers and no family history of cancer (22.9% vs. 4.1%; P = 0.014). In our study, eight out of 10 patients with gBRCA-positive PC received olaparib after platinum-based chemotherapy. The best responses to platinum-based chemotherapy included a complete response in one patient (12.5%) and a partial response in seven patients (87.5%). The median duration of treatment with platinum-based chemotherapy plus olaparib was 17.5 months (8–87 months), and the duration of treatment with olaparib maintenance therapy was 11 months (1–30 months). During olaparib maintenance therapy, three patients showed no disease progression. One of these three patients underwent conversion surgery after receiving olaparib for 12 months. Conclusions: The gBRCA testing should be considered proactively, especially in patients with PC with a family history of HBOC-related cancer. [ABSTRACT FROM AUTHOR]

Breast Cancer Associated Susceptibility Proteins Type 1/2 (BRCA1/2) promote cellular functioning by modulating NRF2-mediated antioxidant signaling. Redox failure in women with BRCA1/2 insufficiency increases the risk for breast/ovarian/uterine cancers. Risk-reducing salpingo-oophorectomy (RRSO) is a prophylactic surgery of the reproductive organs, which is frequently conducted by the age of 40 to lower the occurrence of cancer in women with BRCA1/2 mutations. However, abrupt estrogen decline following RRSO causes ovarian failure, which implicates various cellular physiological processes, resulting in the increased release of free radicals and subsequent severe onset of menopausal symptoms. Comfort measures (e.g., hormonal replacement therapy (HRT) and mindfulness-based stress reduction (MBSR)) may improve chronological menopause-related quality of life, but their specific effects are not clear in women with gene mutations. Aiming to fill the gap, this study used path analysis to examine the effects of HRT and MBSR on menopausal symptoms among RRSO patients (N = 199, mean age = 50.5 ± 6.7 years). HRT directly alleviated the levels of urogenital symptoms (β = −0.195, p = 0.005), which mediated its indirect significant effects on the somatic–vegetative and psychological symptoms of menopause (β = −0.046, −0.067; both p values = 0.004, respectively), especially in BRCA2 carriers and in women who were currently physically active, premenopausal at the time of RRSO, had a high BMI, and had no history of breast cancer. It increased the severity of urogenital symptoms in women with a history of cancer. MBSR, on the other hand, was associated with indirect increases in the intensity of the somatic–vegetative and psychological symptoms of menopause (β = 0.108, 0.029; p = 0.003, 0.033, respectively). It exerted positive direct effects on different menopausal symptoms in multigroup analysis. The results suggest that young women undergoing recent RRSO may benefit from HRT at an individual level, while their need for extensive measures to optimize their psychological wellbeing is ongoing. The adverse effects of MBSR, which are captured in the present study, imply that MBSR may interfere with redox sensitivity associated with estradiol fluctuations in BRCA1/2 carriers. Investigations are needed to test this hypothesis and elaborate on the underlying mechanisms in these women. [ABSTRACT FROM AUTHOR]

Although previous studies have reported that pre-mRNA splicing factors (SFs) are involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), their exact role in promoting HR remains poorly understood. Here, we showed that SART1, an SF upregulated in several types of cancer, promotes DSB end resection, an essential first step of HR. The resection-promoting function of SART1 requires phosphorylation at threonine 430 and 695 by ATM/ATR. SART1 is recruited to DSB sites in a manner dependent on transcription and its RS domain. SART1 is epistatic with BRCA1, a major HR factor, in the promotion of resection, especially transcription-associated resection in the G2 phase. SART1 and BRCA1 accumulate at DSB sites in an interdependent manner, and epistatically counteract the resection blockade posed by 53BP1 and RIF1. Furthermore, chromosome analysis demonstrated that SART1 and BRCA1 epistatically suppressed genomic alterations caused by DSB misrepair in the G2 phase. Collectively, these results indicate that SART1 and BRCA1 cooperatively facilitate resection of DSBs arising in transcriptionally active genomic regions in the G2 phase, thereby promoting faithful repair by HR, and suppressing genome instability. [ABSTRACT FROM AUTHOR]

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials. Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene's reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations. [ABSTRACT FROM AUTHOR]

Homologous recombination (HR) is a highly conserved DNA repair system, in which aberrations can lead to the accumulation of DNA damage and genomic scars known as homologous recombination deficiency (HRD). The identification of mutations in key genes (i.e., BRCA1, and BRCA2 (BRCA)) and the quantification of large-scale structural variants (e.g., loss of heterozygosity) are indicators of the HRD phenotype. HRD is a stable biomarker and remains unchanged during recurrence, but fails to reveal the molecular profile of tumor progression. Moreover, interpretation of the current HRD score lacks comprehensiveness, especially for the HR-proficient group. Poly (ADP-ribose) polymerase (PARP) enzymes play an important role in the repair of DNA single-strand breaks, the blockage of which using PARP inhibitors (PARPi) can generate synthetic lethality in cancer cells with HRD. Although numerous studies have demonstrated that the benefit of PARPi is substantial in ovarian cancer (OC) patients, the efficacy is limited by the development of resistance, and seems to be irrespective of HR and/or BRCA mutation status. Moreover, in addition to improving progressionfree survival, long-term benefit as overall survival brought by PARPi for advanced, recurrent and refractory OC patients remains unclear. Therefore, further investigations are needed to uncover the role of HR genes beyond BRCA and their interactions with other oncogenic pathways, to determine the value of HRD in the recurrent setting, and to identify alternative strategies for the precise management of advanced, refractory OC patients. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is one of the most common malignancies in women. The majority of patients with TNBC have a poor prognosis. The main objective of this study is to review the profile and clinical evidence of the effectiveness of Olaparib in treating TNBC. A literature search was conducted using multiple electronic databases, including PubMed, Google Scholar, JSTOR, and Scopus. The search was focused on articles published up to June 2024, ensuring the inclusion of the latest and relevant studies. The primary objective was to investigate the mechanism of action, toxicity profile, resistance mechanisms, and therapeutic effectiveness of olaparib in the treatment of TNBC, regardless of their prior chemotherapy treatment for metastatic breast cancer, prior platinum-based chemotherapy, or usage of cyclin-dependent kinase 4/6 inhibitors (Balmana et al., 2022). The results of this research suggest that the pharmacological efficacy and safety characteristics of this medication in TNBC patients are similar to those reported in the OlympiAD study. Furthermore, stratification of patients for this medication is possible due to the diagnostic techniques that can predict the presence of the BRCA mutation in order to optimize its efficacies. Additionally, developing and validating new biomarkers beyond BRCA mutations for patient stratification could optimize targeted therapy approaches. [ABSTRACT FROM AUTHOR]

Cancer, a multifactorial disease characterized by uncontrolled cellular proliferation, remains a global health challenge with significant morbidity and mortality. Genomic and molecular aberrations, coupled with environmental factors, contribute to its heterogeneity and complexity. Chemotherapeutic agents like doxorubicin (Dox) have shown efficacy against various cancers but are hindered by dose-dependent cytotoxicity, particularly on vital organs like the heart and brain. Autophagy, a cellular process involved in self-degradation and recycling, emerges as a promising therapeutic target in cancer therapy and neurodegenerative diseases. Dysregulation of autophagy contributes to cancer progression and drug resistance, while its modulation holds the potential to enhance treatment outcomes and mitigate adverse effects. Additionally, emerging evidence suggests a potential link between autophagy, DNA damage, and caretaker breast cancer genes BRCA1/2, highlighting the interplay between DNA repair mechanisms and cellular homeostasis. This review explores the intricate relationship between cancer, Dox-induced cytotoxicity, autophagy modulation, and the potential implications of autophagy in DNA damage repair pathways, particularly in the context of BRCA1/2 mutations. [ABSTRACT FROM AUTHOR]

Breast cancer has the highest diagnosis rate among all cancers. Tumor budding (TB) is recognized as a recent prognostic marker. Identifying genes specific to high-TB samples is crucial for hindering tumor progression and metastasis. In this study, we utilized an RNA sequencing technique, called TempO-Seq, to profile transcriptomic data from breast cancer samples, aiming to identify biomarkers for high-TB cases. Through differential expression analysis and mutual information, we identified seven genes (NOL4, STAR, C8G, NEIL1, SLC46A3, FRMD6, and SCARF2) that are potential biomarkers in breast cancer. To gain more relevant proteins, further investigation based on a protein–protein interaction network and the network diffusion technique revealed enrichment in the Hippo signaling and Wnt signaling pathways, promoting tumor initiation, invasion, and metastasis in several cancer types. In conclusion, these novel genes, recognized as overexpressed in high-TB samples, along with their associated pathways, offer promising therapeutic targets, thus advancing treatment and diagnosis for breast cancer. [ABSTRACT FROM AUTHOR]