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Benign breast tumors are a nonthreatening condition defined as abnormal cell growth within the breast without the ability to invade nearby tissue. However, benign lesions hold valuable biological information that can lead us toward better understanding of tumor biology. In this study, we have used two pathway analysis algorithms, Pathifier and gene set variation analysis (GSVA), to identify biological differences between normal breast tissue, benign tumors and malignant tumors in our clinical dataset. Our results revealed that one‐third of all pathways that were significantly different between benign and malignant tumors were immune‐related pathways, and 227 of them were validated by both methods and in the METABRIC dataset. Furthermore, five of these pathways (all including genes involved in cytokine and interferon signaling) were related to overall survival in cancer patients in both datasets. The cellular moieties that contribute to immune differences in malignant and benign tumors were analyzed using the deconvolution tool, CIBERSORT. The results showed that levels of some immune cells were specifically higher in benign than in malignant tumors, and this was especially the case for resting dendritic cells and follicular T‐helper cells. Understanding the distinct immune profiles of benign and malignant breast tumors may aid in developing noninvasive diagnostic methods to differentiate between them in the future.

Benign breast tumors are a nonthreatening condition defined as abnormal cell growth within the breast without the ability to invade nearby tissue. However, benign lesions hold valuable biological information that can lead us toward better understanding of tumor biology. In this study, we have used two pathway analysis algorithms, Pathifier and gene set variation analysis (GSVA), to identify biological differences between normal breast tissue, benign tumors and malignant tumors in our clinical dataset. Our results revealed that one‐third of all pathways that were significantly different between benign and malignant tumors were immune‐related pathways, and 227 of them were validated by both methods and in the METABRIC dataset. Furthermore, five of these pathways (all including genes involved in cytokine and interferon signaling) were related to overall survival in cancer patients in both datasets. The cellular moieties that contribute to immune differences in malignant and benign tumors were analyzed using the deconvolution tool, CIBERSORT. The results showed that levels of some immune cells were specifically higher in benign than in malignant tumors, and this was especially the case for resting dendritic cells and follicular T‐helper cells. Understanding the distinct immune profiles of benign and malignant breast tumors may aid in developing noninvasive diagnostic methods to differentiate between them in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Vasculogenic mimicry (VM) is an alternative intratumoral microcirculation system that depends on the capacity of tumor cells to reorganize and grow in three-dimensional (3D) channel architectures like the capillaries formed by endothelial cells. Both VM and angiogenesis may coordinately function to feed cancer cells, allowing tumor growth. Long noncoding RNAs (lncRNAs) regulate critical cellular functions in cancer cells, including cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. The lncRNA, known as actin filament-associated protein 1-antisense RNA 1 (AFAP1-AS1), has been described as an oncogene in diverse types of cancers. However, its role in VM and metastasis in triple-negative breast cancer (TNBC) is unknown. Methods Reverse transcription and quantitative polymerase chain reaction (RT‒qPCR) experiments were performed to evaluate the expression of 10 selected lncRNAs from literature in metastatic and nonmetastatic biopsies from TNBC patients. The expression of AFAP1-AS1 was analyzed in Genotype-Tissue Expression Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. The AFAP1-AS1 expression was knocked in TNBC Hs578T cells by transfection of specific siRNAs. Channel-like formation assays were performed using 3D cultures over Matrigel in hypoxia-treated Hs578T cancer cells with diminished expression of AFAP1-AS1. The angiogenesis tests were conducted using human umbilical vein endothelial cells (HUVECs) and AFAP1-AS1- silenced Hs578T cells on 3D cell cultures. The presence of VM (CD31-/PAS+) in tumor tissues from TNBC patients with and without metastasis was assessed through immunohistochemistry using endothelial marker CD31 antibodies and periodic acid-Schiff (PAS) staining. Results Compared with normal mammary tissues, AFAP1-AS1 expression was higher in breast cancer tissues. Moreover, AFAP1-AS1 expression was upregulated in the TNBC subtype compared to receptor-positive breast tumors. In addition, the expression of AFAP1-AS1 was correlated with the expression of the thirteen genes characteristic of a previously reported hypoxia signature. Interestingly, AFAP1-AS1 was upregulated in primary TNBC tumors from patients who developed metastasis compared with the nonmetastatic group. Functional analysis revealed that the knockdown of AFAP1-AS1 in Hs578T cells significantly impaired the hypoxia-induced VM, accompanied by a decrease in the development of 3D channel networks. Similarly, AFAP1-AS1 knockdown counteracts the angiogenic potential of cancer cells, as indicated by a reduction in the number of polygons, sprouting cells, and nodes in HUVEC cells. Remarkably, an increase in CD31-/PAS + staining of 3D channel networks in primary breast tumors from metastatic patients was found compared with the nonmetastatic group. Finally, we found that the number of blood vessels increased in the nonmetastatic group more than in the metastatic cohort. Conclusions Our data suggested that AFAP1-AS1 controls both VM and angiogenesis in Hs578T breast cancer cells and that increased metastasis is associated with VM in TNBC patients.

Abstract Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in the relationship between obesity with cancer. However, the potential of dietary components in modulating this relationship remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. However, there are no reports examining whether genistein has the ability to reduce the effects of obesity on breast tumor development. In this study, we constructed a mammary tumor model in ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Moreover, the effects of genistein on the tumor microenvironment were examined via experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk via coculture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. The impact of genistein extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d-subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and inhibits the expression of inflammatory factors by activating PPAR-γ pathway and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive properties and epithelial‒mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/β-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted the effects of genistein in the coculture system, underscoring the specificity of its action. Our study revealed that genistein can mitigate the adverse effects of obesity on breast cancer by modulating the tumor microenvironment. These findings provide new insights into how genistein intake and a soy-based diet can reduce breast cancer risk.

Somatic mutational profiling is increasingly being used to identify potential targets for breast cancer. However, limited tumor-sequencing data from Hispanic/Latinas (H/L) are available to guide treatment. To address this gap, we performed whole-exome sequencing (WES) and RNA sequencing on 146 tumors and WES of matched germline DNA from 140 H/L women in California. Tumor intrinsic subtype, somatic mutations, copy-number alterations, and expression profiles of the tumors were characterized and compared with data from tumors of non-Hispanic White (White) women in The Cancer Genome Atlas (TCGA). Eight genes were significantly mutated in the H/L tumors including PIK3CA, TP53, GATA3, MAP3K1, CDH1, CBFB, PTEN, and RUNX1; the prevalence of mutations in these genes was similar to that observed in White women in TCGA. Four previously reported Catalogue of Somatic Mutations in Cancer (COSMIC) mutation signatures (1, 2, 3, 13) were found in the H/L dataset, along with signature 16 that has not been previously reported in other breast cancer datasets. Recurrent amplifications were observed in breast cancer drivers including MYC, FGFR1, CCND1, and ERBB2, as well as a recurrent amplification in 17q11.2 associated with high KIAA0100 gene expression that has been implicated in breast cancer aggressiveness. In conclusion, this study identified a higher prevalence of COSMIC signature 16 and a recurrent copy-number amplification affecting expression of KIAA0100 in breast tumors from H/L compared with White women. These results highlight the necessity of studying underrepresented populations.SignificanceComprehensive characterization of genomic and transcriptomic alterations in breast tumors from Hispanic/Latina patients reveals distinct genetic alterations and signatures, demonstrating the importance of inclusive studies to ensure equitable care for patients. See related commentary by Schmit et al., p. 2443.

Background: For effective screening of breast cancer patients for candidates for target therapy with alpelisib, it is necessary to identify activating somatic mutations in the PIK3CA gene by allele specific polymerase chain reaction (PCR); this requires that an optimal list of mutations should be compiled. Aim: To determine the spectrum of somatic mutations in the PIK3CA gene in breast cancer tumors by means of high performance sequencing (next generation sequencing, NGS) and to identify their minimal set for clinical diagnostic testing by allele specific PCR. Methods: Targeted NGS was used to identify mutations in the PIK3CA gene in DNA obtained from paraffin blocks with tumor material from 431 patients with HR+HER2- breast cancer. A set of the most common somatic mutations was also detected by allele specific PCR. Results: We have developed a set of reagents and a protocol for targeted NGS of frequently mutating regions of the PIK3CA and ESR1 genes, which was used to analyze samples from 451 HR+/HER2- breast cancer patients. Clinically significant activating mutations in the PIK3CA gene were found in 32.7% of the samples (141/431). The frequency of the mutant allele ranged from 0.15 to 0.65. Six mutations were most common: c.3140AG p.His1047Arg (69), c.1633GA p.Glu545Lys (32), c.1035TA p.Asn345Lys (12), c.1624GA p.Glu542Lys (9), c.3140AT p.His1047Leu (8), Cys420Arg c.1258TC (3). In total, these mutations amounted to 94.3% (133/141). In 3.5% of the samples (15/431), there were clinically significant somatic mutations in the ESR1 gene: c.1613AG p, Asp538Gly (7), c.1610AC p.Tyr537Ser (6), c.1609TA p.Tyr537Asn (1), c.1610AG p.Tyr537Cys (1), causing resistance to hormone therapy in patients with breast cancer. While rare mutations comprised only 5.7% of our sample, we validated a set of reagents to identify the six mutations described above by allele specific PCR. NGS and PCR were completely concordant. Conclusion: PCR testing of activating somatic mutations of the PIK3CA gene meets the requirements for sensitivity ( 90%) and specificity (100%) for a clinical test and can be used in the selection of patients for targeted therapy with PIK3CA inhibitors.

Breast cancer is a heterogeneous disease, with a subpopulation of tumor cells known as breast cancer stem cells (BCSCs) with self-renewal and differentiation abilities that play a critical role in tumor initiation, progression, and therapy resistance. The tumor microenvironment (TME) is a complex area where diverse cancer cells reside creating a highly interactive environment with secreted factors, and the extracellular matrix. Autophagy, a cellular self-digestion process, influences dynamic cellular processes in the tumor TME integrating diverse signals that regulate tumor development and heterogeneity. Autophagy acts as a double-edged sword in the breast TME, with both tumor-promoting and tumor-suppressing roles. Autophagy promotes breast tumorigenesis by regulating tumor cell survival, migration and invasion, metabolic reprogramming, and epithelial-mesenchymal transition (EMT). BCSCs harness autophagy to maintain stemness properties, evade immune surveillance, and resist therapeutic interventions. Conversely, excessive, or dysregulated autophagy may lead to BCSC differentiation or cell death, offering a potential avenue for therapeutic exploration. The molecular mechanisms that regulate autophagy in BCSCs including the mammalian target of rapamycin (mTOR), AMPK, and Beclin-1 signaling pathways may be potential targets for pharmacological intervention in breast cancer. This review provides a comprehensive overview of the relationship between autophagy and BCSCs, highlighting recent advancements in our understanding of their interplay. We also discuss the current state of autophagy-targeting agents and their preclinical and clinical development in BCSCs.

Automatic ultrasound examination of the breast (3D ultrasound) has become an important tool in the diagnosis of breast cancer. It is believed that 3D ultrasound has high reproducibility, low dependence on the operator, less time spent on obtaining images, and automatic three-dimensional reconstruction of the entire breast.Purpose of the study. To develop indications for 3D ultrasound based on predictive screening models for patients with a low risk of developing breast tumors based on the identification of the most significant risk factors.Patients and methods. A retro-prospective clinical study has been conducted from February 2019 to May 2023. A total of 2794 patients were included in the study. All patients underwent clinical examination, palpation, collected information on socio-demographic data and potential risk factors for breast cancer, and 2D ultrasound was also performed. The group under the age of 40 included 1,511 patients, of whom 628 underwent 3D ultrasound. The sample of 40 years and older included 1,283 patients, 655 of whom underwent 3D ultrasound. Mammography was performed in patients aged 40 and older. Quantitative and qualitative indicators of anamnesis and clinical examination, as well as MMH results in patients over 40 years old, were recorded. Based on these data, a logistic regression was compiled, followed by the selection of the most significant model by cutting off insignificant factors according to the p-level of significance and presenting the model as a ROC curve.Results. The most significant risk factors for the detection of breast cancer were identified. Based on their screening with 3D ultrasound in a group up to 40 years of age, it can be used in 95.96 % and is not indicated in 4.04 %. The presented model in the group up to 40 years worked correctly in 99.21 %. While screening with 3D ultrasound in a group of 40 years and older in 84.26 % is appropriate and not indicated in 15.74 %. The presented model worked correctly in 97.12 %.Conclusion. The study identified important pre-diagnostic factors for the choice of a diagnostic algorithm for breast examination in women of different age groups, and determined the indications for 3D ultrasound. The developed algorithms will help optimize screening and referral for additional examinations, which is of practical importance for improving diagnostics and optimizing healthcare resources.

The alarming liability of breast cancer, mainly among younger Saudi women, has been attributed to diverse factors requiring a manageable valuation. Therefore, this study aimed to assess the types of tumors and breast cancer presentation stages in Northern Saudi Arabia. In the present study, retrieved data regarding breast biopsies were received from the Department of Pathology at King Salman Hospital, Hail, Northern Saudi Arabia. Included data referring to breast cancer biopsies patients (including 131 females and two males) diagnosed during the period from November 2019 to November 2020. Out of the 133 patients, breast cancer was diagnosed in 49/133(36.8%) patients included 45/49(91.8%) invasive ductal carcinoma (IDC), 2/49(4.1%) invasive lobular carcinoma (ILC), and 2/49(4.1%) papillary carcinoma. The remaining 84 benign breast lesions included 40/84(47.6%) fibroadenoma, 11/84(13%) ductal hyperplasia, 9/84(10.7%) fibrocystic disease, 8/84(9.5%) adenosis, 4/84(4.8%) chronic mastitis, 3/84(3.6%) breast abscess & intraductal papilloma, 2/84(2.4%) duct ectasia & phylloides tumor, and 1/84(1.2%) lactating adenoma & lipoma. Breast cancer is highly prevalent in Northern Saudi Arabia with predominantly invasive ductal carcinoma. There is an increase in the incidence of younger patients with advanced stages of initial presentation. Fibroadenoma is the commonest benign breast lesion, followed by fibrocystic diseases in Northern Saudi Arabia.

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype, with a poor survival rate compared to others subtypes. For a long time, chemotherapy was the only systemic treatment for TNBC, and the identification of actionable molecular targets might ultimately improve the prognosis for TNBC patients. We performed a genome-wide analysis of DNA methylation at CpG islands on a collection of one hundred ten breast carcinoma samples and six normal breast tissue samples using reduced representation bisulfite sequencing with the XmaI restriction enzyme (XmaI-RRBS) and identified a subset of TNBC samples with significant hypomethylation at the LTB4R/LTB4R2 genes' CpG islands, including CpG dinucleotides covered with cg12853742 and cg21886367 HumanMethylation 450K microarray probes. Abnormal DNA hypomethylation of this region in TNBC compared to normal samples was confirmed by bisulfite Sanger sequencing. Gene expression generally anticorrelates with promoter methylation, and thus, the promoter hypomethylation detected and confirmed in our study might be revealed as an indirect marker of high LTB4R/LTB4R2 expression using a simple methylation-sensitive PCR test. Analysis of RNA-seq expression and DNA methylation data from the TCGA dataset demonstrates that the expression of the LTB4R and LTB4R2 genes significantly negatively correlates with DNA methylation at both CpG sites cg12853742 (R = −0.4, p = 2.6 × 10−6; R = −0.21, p = 0.015) and cg21886367 (R = −0.45, p = 7.3 × 10−8; R = −0.24, p = 0.005), suggesting the upregulation of these genes in tumors with abnormal hypomethylation of their CpG island. Kaplan–Meier analysis using the TCGA-BRCA gene expression and clinical data revealed poorer overall survival for TNBC patients with an upregulated LTB4R. To this day, only the leukotriene inhibitor LY255283 has been tested on an MCF-7/DOX cell line, which is a luminal A breast cancer molecular subtype. Other studies compare the effects of Montelukast and Zafirlukast (inhibitors of the cysteinyl leukotriene receptor, which is different from LTB4R/LTB4R2) on the MDA-MB-231 (TNBC) cell line, with high methylation and low expression levels of LTB4R. In our study, we assess the therapeutic effects of various drugs (including leukotriene receptor inhibitors) with the DepMap gene effect and drug sensitivity data for TNBC cell lines with hypomethylated and upregulated LTB4R/LTB4R2 genes. LY255283, Minocycline, Silibinin, Piceatannol, Mitiglinide, 1-Azakenpaullone, Carbetocin, and Pim-1-inhibitor-2 can be considered as candidates for the additional treatment of TNBC patients with tumors demonstrating LTB4R/LTB4R2 hypomethylation/upregulation. Finally, our results suggest that the epigenetic status of leukotriene B4 receptors is a novel, potential, predictive, and prognostic biomarker for TNBC. These findings might improve individualized therapy for TNBC patients by introducing new therapeutic adjuncts as anticancer agents. [ABSTRACT FROM AUTHOR]

Cancer is a critical global public health problem with meager median survival. It is therefore quite essential to detect this disease at an early stage to improve diagnostic results and consequently avoid serious complications. For this purpose, various researchers have implemented automated methods with the use of different medical imaging modalities. Accordingly, the expansion of deep learning techniques grants opportunities to enhance diagnosis, cure, and prevention. In this study, a diagnostic system for accurate classification of ultrasound breast abnormalities based on the powerful ResNet-50 CNN is proposed with the aim of providing early detection of breast cancer decease. The contribution of this work lies in the novel approach taken to improve the performance of the ResNet50 model in the classification of ultrasound breast cancer images. Transfer learning allows for the model to leverage pre-existing knowledge, while the application of data augmentation techniques enhances the diversity and quality of the training data. Additionally, the optimization of the batch size as a hyperparameter ensures that the model is able to effectively learn from the training data, leading to improved accuracy and efficiency in the classification process. This approach is crucial in the early detection and treatment of breast cancer. Quantitative and qualitative evaluations have been detailed in this study using Breast Ultrasound Dataset BUSI. Our presented work shows interesting results in terms of accuracy, specificity, sensitivity, and AUC which exceed the performance of other compared works. Moreover, the proposed method helps boost the clinical diagnosis of breast cancer. It may integrate a radiologist network, allowing them to constantly follow up on the patient's medical history. [ABSTRACT FROM AUTHOR]

Loss of BRCA2 (breast cancer 2) is lethal for normal cells. Yet it remains poorly understood how, in BRCA2 mutation carriers, cells undergoing loss of heterozygosity overcome the lethality and undergo tissue-specific neoplastic transformation. Here, we identified mismatch repair gene mutL homolog 1 (MLH1) as a genetic interactor of BRCA2 whose overexpression supports the viability of Brca2-null cells. Mechanistically, we showed that MLH1 interacts with Flap endonuclease 1 (FEN1) and competes to process the RNA flaps of Okazaki fragments. Together, they restrained the DNA2 nuclease activity on the reversed forks of lagging strands, leading to replication fork (RF) stability in BRCA2-deficient cells. In these cells, MLH1 also attenuated R-loops, allowing the progression of stable RFs, which suppressed genomic instability and supported cell viability. We demonstrated the significance of their genetic interaction by the lethality of Brca2-mutant mice and inhibition of Brca2-deficient tumor growth in mice by Mlh1 loss. Furthermore, we described estrogen as inducing MLH1 expression through estrogen receptor [alpha] (ER[alpha]), which might explain why the majority of BRCA2 mutation carriers develop ER- positive breast cancer. Taken together, our findings reveal a role of MLH1 in relieving replicative stress and show how it may contribute to the establishment of BRCA2-deficient breast tumors., Introduction Some of the well-established breast and ovarian cancer susceptibility genes, such as breast cancer 1 (BRCA1), BRCA2, and PALB2, encode proteins that play a key role in repairing double-strand [...]

Background: Compared to conventional 2D mammography, digital breast tomosynthesis (DBT) offers greater breast lesion detection rates. Ring-like hypodense artifacts surrounding dense lesions are a common byproduct of DBT. This study’s purpose was to assess whether minuscule changes spanning this halo—termed the “broken halo sign”—could improve lesion classification. Methods: This retrospective study was approved by the local ethics review board. After screening 288 consecutive patients, DBT studies of 191 female participants referred for routine mammography with a subsequent histologically verified finding of the breast were assessed. Examined variables included patient age, histological diagnosis, architectural distortion, maximum size, maximum halo depth, conspicuous margins, irregular shape and broken halo sign. Results: While a higher halo strength was indicative of malignancy in general (p = 0.031), the broken halo sign was strongly associated with malignancy (p < 0.0001, odds ratio (OR) 6.33), alongside architectural distortion (p = 0.012, OR 3.49) and a diffuse margin (p = 0.006, OR 5.49). This was especially true for denser breasts (ACR C/D), where the broken halo sign was the only factor predicting malignancy (p = 0.03, 5.22 OR). Conclusion: DBT-associated halo artifacts warrant thorough investigation in newly found breast lesions as they are associated with malignant tumors. The “broken halo sign”—the presence of small lines of variable diameter spanning the peritumoral areas of hypodensity—is a strong indicator of malignancy, especially in dense breasts, where architectural distortion may be obfuscated due to the surrounding tissue.

Breast cancer is the most common malignancy among women, and early diagnosis and targeted therapy have garnered significant attention. Non-coding RNAs have emerged as potential diagnostic, prognostic, and treatment biomarkers for breast cancer. This study aimed to evaluate the expression of non-coding RNAs, specifically miR-506 and circular RNA 000284, and their target gene SNAIL-2 in breast tumors compared to normal controls. The study also focused on clinicopathological characteristics, and plasma was monitored for expression of circ0000284 to identify a possible accessible cancer-related marker. Using the SYBR-Green Real-time PCR technique, total RNA was extracted from 80 breast tumors and normal adjacent tissues, and circ0000284, miR-506, and SNAIL2 expression were analyzed. The results showed overexpression, down-regulation, and up-regulation of circRNA 000284, miR-506, and SNAIL-2 gene, respectively. These expression changes were associated with advanced stages of the disease and lymph nodal involvement, which are signs of a poor prognosis. Additionally, a positive direct correlation was observed between circRNA000284 expression in tumors and plasma. Moreover, it was discovered that circ-0000284 sponged miR-506, causing up-regulation of SNAIL-2 as its mRNA target. The upregulation of SNAIL-2 as an epithelial-mesenchymal-transition (EMT)factor leads to poor prognosis in breast cancer and is epigenetically regulated by miR-506 and circRNA 000284. Therefore, the overexpression of circRNA000284 in plasma could be considered an indicator of lymph nodal involvement and advanced stages of cancer, and nominated as a poor prognostic biomarker for future considerations.

ObjectiveTo examine amide proton transfer-weighted (APTw) combined with diffusion weighed (DWI) and dynamic contrast enhanced (DCE) MRI for early prediction of pathological response to neoadjuvant chemotherapy in invasive breast cancer.MaterialsIn this prospective study, 50 female breast cancer patients (49.58 ± 10.62 years old) administered neoadjuvant chemotherapy (NAC) were enrolled with MRI carried out both before NAC (T0) and at the end of the second cycle of NAC (T1). The patients were divided into 2 groups based on tumor response according to the Miller-Payne Grading (MPG) system. Group 1 included patients with a greater degree of decrease in major histologic responder (MHR, Miller-Payne G4-5), while group 2 included non-MHR cases (Miller-Payne G1-3). Traditional imaging protocols (T1 weighted, T2 weighted, diffusion weighted, and DCE-MRI) and APTw imaging were scanned for each subject before and after treatment. APTw value (APTw0 and APTw1), Dmax (maximum diameter, Dmax0 and Dmax1), V (3D tumor volume, V0 and V1), and ADC (apparent diffusion coefficient, ADC0 and ADC1) before and after treatment, as well as changes between the two times points (ΔAPT, ΔDmax, ΔV, ΔADC) for breast tumors were compared between the two groups.ResultsAPT0 and APT1 values significantly differed between the two groups (p = 0.034 and 0.01). ΔAPTw values were significantly lower in non-MHR tumors compared with MHR tumors (p = 0.015). ΔDmax values were significantly higher in MHR tumors compared with non-MHR tumors (p = 0.005). ADC0 and ADC1 values were significantly higher in MHR tumors than in non-MHR tumors (p = 0.038 and 0.035). AUC (Dmax+DWI + APTw) = AUC (Dmax+APTw) > AUC (APTw) > AUC (Dmax+DWI) > AUC (Dmax).ConclusionAPTw imaging along with change of tumor size showed a significant potential in early prediction of MHR for NAC treatment in breast cancer, which might allow timely regimen refinement before definitive surgical treatment.

The TP53 tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. We developed an autochthonous somatic K14-Cre driven TNBC mouse model with p53R172H and p53R245W mutations in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53. These mice develop TNBCs with a median latency of 1 y. Deletion of mutant p53R172H or p53R245W in vivo in these tumors blunts their tumor growth and significantly extends survival of mice. Downstream analyses revealed that deletion of mutant Trp53 activated the cyclic GMP-AMP Synthase-Stimulator of Interferon Genes pathway but did not cause apoptosis implicating other mechanisms of tumor regression. Furthermore, we determined that only tumors with stable mutant p53 are dependent on mutant p53 for growth. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the effects of BP and doxorubicin (DOX) on 4T1 tumor cells in a mouse model. Materials and Methods: After inducing breast tumors, 70 4T1-tumor-bearing BALB/c mice were divided into seven groups (n = 10/group). The groups were treated with DOX and BP for 35 days. On the 36th day, blood was taken from the heart, and serum was separated to measure levels of cytokines, estrogen, progesterone, testosterone, and nitric oxide. Antioxidant enzyme activities, as well as tissue ferric-reducing antioxidant power (FRAP) and malondialdehyde (MDA) levels, were evaluated. The expression of apoptotic genes and metastasis was measured using real-time polymerase chain reaction (PCR), while the expression of apoptotic proteins was evaluated using Western blotting. Finally, Ki-67 and p-53 were examined using immunohistochemistry to determine apoptosis. Results: The study found that BP, with its synergistic effects with DOX, reduced the volume of tumors and increased the expression of apoptotic genes and proteins. In a dose-dependent manner, groups receiving BP and DOX with their synergistic effects reduced the level of estrogen and nitric oxide and also reduced the level of pro-inflammatory cytokines. BP along with DOX increased serum interferon-γ (IFN-γ) levels. Tumor tissue FRAP and thiobarbituric acid reactive substances (TBARS) levels increased in BP-treated groups. Ki-67 and Bcl-2 proliferation markers levels decreased, and p53 levels increased in 4T1-breast tumors. Conclusion: The study concluded that BP with its synergistic effects along with DOX has the ability to suppress the growth of tumors and can also inhibit the oxidative damage of DOX. [ABSTRACT FROM AUTHOR]

Abstract Background The interface zone, area around invasive carcinoma, can be thought of as the actual tissue of the tumor microenvironment with precedent alterations for tumor invasion. However, the heterogeneity and characteristics of the microenvironment in the interface area have not yet been thoroughly explored. Methods For in vitro studies, single-cell RNA sequencing (scRNA-seq) was used to characterize the cells from the tumor zone, the normal zone and the interface zone with 5-mm-wide belts between the tumor invasion front and the normal zone. Through scRNA-seq data analysis, we compared the cell types and their transcriptional characteristics in the different zones. Pseudotime, cell–cell communication and pathway analysis were performed to characterize the zone-specific microenvironment. Cell proliferation, wound healing and clone formation experiments explored the function of differentially expressed gene BMPR1B, which were confirmed by tumor models in vivo. Results After screening, 88,548 high-quality cells were obtained and identified. Regulatory T cells, M2 macrophages, angiogenesis-related mast cells, stem cells with weak DNA repair ability, endothelial cells with angiogenic activity, fibroblasts with collagen synthesis and epithelial cells with proliferative activity form a unique tumorigenic microenvironment in the interface zone. Cell–cell communication analysis revealed that there are special ligand–receptor pairs between different cell types in the interface zone, which protects endothelial cell apoptosis and promotes epithelial cell proliferation and migration, compared to the normal zone. Compared with the normal zone, the highly expressed BMPR1B gene promotes the tumorigenic ability of cancer cells in the interface zone. Conclusions Our work identified a unique tumorigenic microenvironment of the interface zone and allowed for deeper insights into the tumor microenvironment of breast cancer that will serve as a helpful resource for advancing breast cancer diagnosis and therapy.

The addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early-stage, HER2-positive breast cancer. Nonetheless, up to 50% of patients have residual disease after treatment, while others are likely overtreated. Here, we performed multiplex spatial proteomic characterization of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial sampled pre-treatment, after 14-21 d of HER2-targeted therapy and at surgery. We demonstrated that proteomic changes after a single cycle of HER2-targeted therapy aids the identification of tumors that ultimately undergo pCR, outperforming pre-treatment measures or transcriptomic changes. We further developed and validated a classifier that robustly predicted pCR using a single marker, CD45, measured on treatment, and showed that CD45-positive cell counts measured via conventional immunohistochemistry perform comparably. These results demonstrate robust biomarkers that can be used to enable the stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy, with implications for tailoring subsequent therapy.

Introduction Breast cancer is the most common cancer in women in India and accounts for 14% of all cancers in women. Rise in mortality is due to lack of awareness and proper screening. Mammography and presently available serum biomarkers have low sensitivity and specificity. In our quest to identify a better biomarker, we studied mammaglobin (MAM) in patients with breast cancer and benign breast tumors. Aim To evaluate serum mammaglobin in breast cancer patients and compare it with benign breast tumor patients and healthy controls. To compare it with existing biomarkers serum carcinoembryonic antigen (CEA) and cancer antigen 15–3 (CA 15–3). Materials and methods: This is a cross-sectional, case–control study of 77 subjects, of which 27 were breast cancer patients, 20 benign breast tumor patients, and 30 healthy controls. Serum CEA and CA15–3 were estimated by electrochemiluminescence immunoassay (ECLIA) and mammaglobin (MAM) by enzyme-linked immunosorbent assay (ELISA). Results Mammaglobin and CEA levels were elevated in breast cancer patients, followed by benign breast tumors when compared with controls (P < 0.000001). Mammaglobin showed 81.5% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 88.9% negative predictive value (NPV). CEA showed 88.9% sensitivity, 82.5% specificity, 77.4% PPV, and 91.7% NPV. The area under the curve was the highest for MAM (0.892), followed by CEA (0.889) and CA 15–3 (0.555). CA15–3 showed poor diagnostic efficacy. Combined receiver operating characteristic (ROC) curve of the biomarkers MAM and CEA had an AUC of 0.913. Conclusion Mammaglobin proved to be an efficacious biomarker in diagnosing breast cancer. [ABSTRACT FROM AUTHOR]

Radio-frequency (RF) ablation is a reliable technique for the treatment of deep-seated malignant tumors, including breast carcinoma, using high ablative temperatures. The paper aims at a comparative analysis of the specific absorption rate and temperature distribution during RF ablation with regard to different female breast tumors. In the study, four tumor models equivalent to an irregular tumor were considered, i.e., an equivalent sphere and ellipsoid with the same surfaces and volumes as the irregular tumor and an equivalent sphere and ellipsoid inscribed in the irregular tumor. An RF applicator with a specific voltage, operating at 100 kHz inserted into the anatomically correct female breast, was applied as a source of electromagnetically induced heat. A conjugated Laplace equation with the modified Pennes equation was used to obtain the appropriate temperature gradient in the treated area. The levels of power dissipation in terms of the specific absorption rate (SAR) inside the naturalistically shaped tumor, together with the temperature profiles of the four simplified tumor models equivalent to the irregular one, were determined. It was suggested that the equivalent tumor models might successfully replace a real, irregularly shaped tumor, and the presented numeric methodology may play an important role in the complex therapeutic RF ablation process of irregularly shaped female breast tumors. [ABSTRACT FROM AUTHOR]

Breast radiologists encounter unusual lesions, which may not be well described in the literature. Previously based on histologic and molecular classifications, the World Health Organization (WHO) classification of tumors has become increasingly multidisciplinary. Familiarity with imaging features and basic pathology of infrequent breast lesions, as well as their current classification according to the WHO, may help the radiologist evaluate biopsy results for concordance and help direct the management of uncommon breast lesions. This review article provides a case-based review of imaging features and WHO histologic classification of rare breast tumors. [ABSTRACT FROM AUTHOR]

Background: A non-histone nuclear protein tightly associated with the cell cycle is Ki-67 which is seen in cell cycles phase mid-G1, G2, mitosis, and S phase. However, Ki-67 is not seen in early G1, G0, and resting or quiescent cells. Ki-67 is a reliable indicator of prognosis and proliferation of the tumor in subjects with carcinoma breast. Aims: The present clinical study was conducted to assess the association between the proliferative activity of breast-tumors evaluated with Ki-67 scores and the relationship between Ki-67 scores and malignant potential of the breast tumors. Methods: The present prospective clinical study included 374 female subjects of the FNAC from subjects having palpable breast lesions. The second pass was given, whereas, the first pass was used for either LBC or conventional smear. Several criteria were used to compare representative LBC and conventional smear. Individual scoring of each criterion was done followed by statistical evaluation. Ki-67 proliferation index was assessed for conventional smears and LBC. Results: For conventional smear diagnosis, benign cases reported were 253 were negative for Ki-67 immunostaining. Among uncertain cases, 4 cases were negative for Ki-67 immunostaining were 1 case had a low Ki-67 proliferative index and 14 had a high Ki-67 proliferative index. On conventional smear, 74 cases were seen as malignant whereas all the cases had a high Ki-67 proliferative index. In the Ki-67 proliferation index and diagnosis on LBC (liquid-based cytology), it was seen that there were 253 cases reported as benign on LBC which were negative. In the present study, 19 subjects were reported as uncertain, among which 4 cases were negative for Ki-67 immunostaining, 1 subject had low Ki-67 proliferative index, and 14 specimens had high Ki-67 proliferative index. For the distribution of cases based on Ki-67 proliferation index in the study subjects, the number of cases reported with a score 0 i.e., negative for Ki-67 was 257, number of cases reported with a score of 1 i.e., the low proliferative score for Ki-67 were 01, and number of cases reported with a score 2 i.e., the high proliferative index for Ki-67 were 88. Conclusion: Within its limitations, the present study concludes that the Ki-67 proliferative index is a reliable indicator of prognosis and proliferation of the tumor in subjects with carcinoma breasts. [ABSTRACT FROM AUTHOR]

Simple Summary: HER2-low breast cancer is a newly recognized subtype that has shown promising responses to treatment with antibody–drug conjugates (ADCs). However, there is still little known about its clinical and molecular characteristics. In this study, we examined the clinical and pathological features, survival rates, and expression of HER2-related genes in Colombian patients with HER2-low breast cancer, comparing them to HER2-negative and positive groups. We found that HER2-low tumors were better differentiated and had a lower proliferation index compared to HER2-positive tumors. Additionally, compared to HER2-negative cases, HER2-low patients had higher mRNA expression of the ERBB2 gene and longer overall survival rates. Despite these findings, there were no significant differences in survival when adjusted for estrogen receptor status and clinical stage. These results highlight the need for further research on HER2-low breast cancer to optimize treatment strategies for this unique group. HER2-low tumors have shown promise in response to antibody–drug conjugates (ADCs) in recent clinical trials, underscoring the need to characterize this group's clinical phenotype. In this study, we aimed to explore the clinicopathological features, survival rates, and HER2 amplicon mRNA expression of women affected with HER2-low breast cancer, compared with HER2-negative and HER2-positive groups. We included 516 breast cancer patients from Colombia, for whom we compared clinicopathological features, mRNA expression of three HER2 amplicon genes (ERBB2, GRB7 and MIEN1), survival and risk of mortality between HER2-low cases (1+ or 2+ with negative in situ hybridization (ISH) result) with HER2-positive (3+ or 2+ with positive ISH test) and HER2-negative (0+) cases. A higher proportion of patients with better-differentiated tumors and a lower proliferation index were observed for HER2-low tumors compared to the HER2-positive group. Additionally, HER2-low tumors showed higher mRNA expression of the ERBB2 gene and longer overall survival rates compared to HER2-negative cases. Nonetheless, a Cox-adjusted model by ER status and clinical stage showed no statistically significant differences between these groups. Our results show differences in important clinicopathological features between HER2-low and both HER2-positive and negative tumors. Given this unique phenotype, it is crucial to evaluate the potential advantages of ADC therapies for this emerging subtype of breast cancer. [ABSTRACT FROM AUTHOR]

Introduction Breast cancer is the most common cancer in women in India and accounts for 14% of all cancers in women. Rise in mortality is due to lack of awareness and proper screening. Mammography and presently available serum biomarkers have low sensitivity and specificity. In our quest to identify a better biomarker, we studied mammaglobin (MAM) in patients with breast cancer and benign breast tumors.

Breast cancer risk factors include lifestyle, genetic–hormonal influences, and viral infections. Human papillomavirus (HPV), known primarily as the etiological agent of cervical cancer, also appears active in breast carcinogenesis, as evidenced in our study of 56 patients from northeastern Brazil. We assessed the clinical and sociodemographic characteristics, correlating them with various breast cancer tumor types. HPV detection involved amplifying the L1 region, with viral load measured using the E2/E6 ratio and viral activity indicated by E5 oncogene expression. Predominantly, patients over 56 years of age with healthy lifestyles showed a high incidence of invasive ductal carcinoma and triple-negative breast cancer. HPV was detected in 35.7% of cases, mostly HPV16, which is associated with high viral loads (80 copies per cell) and significant E5 expression. These results hint at a possible link between HPV and breast carcinogenesis, necessitating further studies to explore this association and the underlying viral mechanisms.

Abstract Background Up to 40% of patients with estrogen receptor-positive (ER+) breast cancer experience relapse. This can be attributed to breast cancer stem cells (BCSCs), which are known to be involved in therapy resistance, relapse, and metastasis. Therefore, there is an urgent need to identify genes/pathways that drive stem-like cell properties in ER+ breast tumors. Methods Using single-cell RNA sequencing and various bioinformatics approaches, we identified a unique stem-like population and established its clinical relevance. With follow-up studies, we validated our bioinformatics findings and confirmed the role of ER and NFĸB in the promotion of stem-like properties in breast cancer cell lines and patient-derived models. Results We identified a novel quiescent stem-like cell population that is driven by ER and NFĸB in multiple ER+ breast cancer models. Moreover, we found that a gene signature derived from this stem-like population is expressed in primary ER+ breast tumors, endocrine therapy-resistant and metastatic cell populations and predictive of poor patient outcome. Conclusions These findings indicate a novel role for ER and NFĸB crosstalk in BCSCs biology and understanding the mechanism by which these pathways promote stem properties can be exploited to improve outcomes for ER+ breast cancer patients at risk of relapse.

Parabens are a category of antimicrobial preservatives that may play a role in the etiology and epidemiology of cancers. Parabens are employed in a wide range of pharmaceuticals, cosmetics, personal care products, and processed foods. Parabens are thought to influence the evolution of carcinogenesis in breast cancer by acting as genotoxicants, cell proliferation factors, migratory and metastatic activators, and hyper-accumulate in breast cancer cells. A goal of this study was to characterize the relationship between paraben contamination and the incidence of both malignant and benign breast tumors in patients attending Hojati and Khanavadeh hospitals, in the city of Isfahan, Iran. A second goal was to examine the relationship among methyl, ethyl, n-propyl, and n-butyl paraben concentrations, exposure factors for parabens, and risk factors for breast cancer among patients with cancerous and non-cancerous breast tissues. A reference for median concentration of total parabens in healthy, non-tumor tissue is 160 ng/g (Barr et al., 2012). In this study, benign breast tumors had a mean concentration of 357 ng/g of total parabens. In contrast, malignant breast tissue had a mean concentration of 472 ng/g(mean) total parabens. Malignant tumors had higher n-propyl paraben (β=39.52; p=0.039) and n-butyl paraben (β=43.92; p=0.028) concentrations among the patients with a positive human epidermal growth factor receptor2 (HER2) rather than the patients with a negative HER2. Results indicated that higher age was associated with higher n-butyl paraben concentration (β=1.97; p=0.012) among the patients with malignant tumors. Moreover, the body mass index (BMI) had a positive relationship with ethyl paraben concentration (β=6.37; p= 0.030) among patients with malignant tumors. The questionnaire-survey used in this study was unable to discern why there was higher accumulation of parabens in the tumor-tissue types. Larger population-based longitudinal studies are necessary to confirm this association and to evaluate the association of parabens with clinical indicators of breast cancer and mortality.

The concept of BRCAness was developed because of similarities between sporadic and hereditary breast cancer. BRCAness defines the pathogenesis and treatment sensitivity of many types of cancer, as well as the presence of a defect in the homologous recombination repair of tumor cells simulating the loss of BRCA1 or BRCA2, as in the presence of germline mutations. The question of treatment effectiveness for BRCA-like tumors is controversial and open. Thus, the aim of this work was to study the effectiveness of neoadjuvant chemotherapy (NAC) in BRCA-deficient breast cancer patients without germline mutations. The study involved 130 patients with breast cancer in stages IIA–IIIB. The treatment regimen included neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy. The materials used were tumor samples from before and after chemotherapy. DNA and RNA were isolated from the tumor material. RNA was used to assess the expression level of BRCA1, while DNA was used for methyl-sensitive PCR. A microarray analysis was performed on high-density DNA chips from an Affymetrix CytoScanTM HD Array to assess DNA copy number aberration (CNA status) and loss of heterozygosity. A statistical analysis was performed using the Statistica 8.0 application package. It was noted that the existence of copy number aberrations in genes was statistically significantly associated with tumor treatment response and disease prognosis. Patients with partial regression had a statistically significantly higher amount of deletion than patients without an objective response (5/25 patients; 16%), as shown in the general sample of patients (52.9% versus 27.1%, respectively) at p = 0.0001 and in patients treated with anthracycline-containing regimen (p = 0.0001). In addition, it was shown that patients with BRCA1 deletion had higher rates of metastatic-free survival (log rank test, p = 0.009). BRCAness patients had a higher rate of 5-year metastatic survival, but not of treatment efficacy. The prospective study showed the positive effect of assessing the BRCAness phenotype of a tumor before treatment and of prescribing personalized NAC regimens. The objective response rate was statistically significantly more often observed in the group of patients with personalized chemotherapy (85.0% (34/40 patients) versus 62.3% (56/90 patients); p = 0.007). Despite the controversial effectiveness of BRCA-like tumor treatment, our data showed high predictive and prognostic significance of the BRCAness phenotype for the personalization of platinum and taxane regimens. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of gadopentetate dimeglumine enhancement on the apparent diffusion coefficient (ADC) values and the diagnostic efficacy of ADC values in breast tumors. Methods The ADC values of 272 histologically confirmed breast tumors before and after contrast enhancement were retrospectively analyzed. The ADC values between benign, invasive, and non-invasive breast tumors before, at 3 minutes, and 13 minutes after enhancement were compared using receiver operating characteristic (ROC) curve analysis. Results The ADC values of invasive breast cancer were significantly greater (P<0.001) before [(0.999±0.167)x10-3 mm²/s] than that at 3 minutes after [(0.934±0.165) x10-3 mm²/s] contrast enhancement. There was no significant difference in ADC values between the other breast tumors before and after enhancement. The cut-off ADC values of 1.23x 10-3 mm²/s before enhancement had 92.3% sensitivity and 96.3% specificity for differentiating benign and malignant tumors compared to 80.8% sensitivity and 100% specificity at cut-off ADC value of 1.31x10-3 mm²/s 3 minutes after enhancement. The cut-off ADC values of 1.22x10-3 mm² /s before enhancement had 95.7% sensitivity and 91.3% specificity for differentiating benign and malignant tumors compared to 92.4% sensitivity and 95.0% specificity at cut-off ADC value of 1.30 x10-3 mm²/s 13 minutes after enhancement. The areas under the ROC curves were all greater than 0.95. Conclusion The ADC value of invasive breast cancer decreased at 3 minutes after enhancement without affecting the diagnostic efficacy of breast tumors. The acquisition of diffusion weighted imaging sequence at 3 minutes instead of 13 minutes after enhancement can reduce the total examination time. [ABSTRACT FROM AUTHOR]

Phyllodes tumors, World Health Organization fibroepithelial tumors, are classified as benign, borderline, or malignant based on histopathology. Phyllodes must be distinguished from benign fibroadenomas, also WHO fibroepithelial tumors. The distinction of phyllodes from fibroadenomas can be challenging clinically, as these tumors may mirror one another. Here, we present 2 cases, classic clinical and imaging examples of benign and malignant phyllodes, to review the current epidemiology, classification, diagnosis, and treatment of phyllodes tumors.

Breast cancer risk factors include lifestyle, genetic–hormonal influences, and viral infections. Human papillomavirus (HPV), known primarily as the etiological agent of cervical cancer, also appears active in breast carcinogenesis, as evidenced in our study of 56 patients from northeastern Brazil. We assessed the clinical and sociodemographic characteristics, correlating them with various breast cancer tumor types. HPV detection involved amplifying the L1 region, with viral load measured using the E2/E6 ratio and viral activity indicated by E5 oncogene expression. Predominantly, patients over 56 years of age with healthy lifestyles showed a high incidence of invasive ductal carcinoma and triple-negative breast cancer. HPV was detected in 35.7% of cases, mostly HPV16, which is associated with high viral loads (80 copies per cell) and significant E5 expression. These results hint at a possible link between HPV and breast carcinogenesis, necessitating further studies to explore this association and the underlying viral mechanisms. [ABSTRACT FROM AUTHOR]

BRCA1 variants are extensively associated with increased risk of breast cancer. Early detection and screening of variants is still rare in developing countries. Here, we investigated six BRCA1 variants in 300 subjects from Pakistani population using tetra amplification‐refractory mutation system (T‐ARMS) PCR. Our results indicate significant association of BRCA1 variants rs8176237 (AA; OR 8.2, 95% CI 3.02–22.64, p < 0.0001), rs1060915 (CC; OR 4.29, 95% CI 1.94–9.48, p = 0.0003), and rs799912 (TT; OR 3.16, 95% CI 1.44–6.94, p = 0.004) with up to 8‐fold increased odds of breast cancer under recessive model. Furthermore, BRCA1 haplotypes AGCACG and AGCCCT were associated with up to 18% breast cancer cases (p < 0.05). Additionally, we found association of these variants with up to 11‐fold increased odds of benign breast tumors. Linkage disequilibrium (LD) block‐wise analysis revealed haplotypes GCAC and ATAC were associated with significantly increased risk. To our knowledge, this is the first study that identifies the association of these BRCA1 variants with breast tumors in Pakistani population. In conclusion, BRCA1 variants investigated in the present study are associated with high odds of benign‐ and malignant breast tumors. Studies with bigger sample size may help early detection and screening to reduce the odds of breast cancer. [ABSTRACT FROM AUTHOR]