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PURPOSE Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates ( P < .0001) and 3-year overall survival (OS) rates ( P < .0001). TNBC was associated with increased risk for visceral metastases ( P = .0005), lower risk for bone recurrence ( P = .027), and shorter postrecurrence survival ( P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival ( P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC ( P < .0001). CONCLUSION Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

BACKGROUND/AIMS: There is a pressing need for new therapies for the most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC). Tenascin-C (TN-C) codes for a tumor microenvironment-specific protein, which promotes apoptosis evasion and cell proliferation. The aim of this study was to knock down TN-C by using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system to induce cancer cell apoptosis and stunt cell proliferation, laying the grounds for a new gene therapy approach in TNBC.MATERIALS and METHODS: The human TNBC cell line, MDA-MB-231 cells were transfected by TN-C-specific CRISPR/Cas9 plasmids. TN-C messenger RNA levels were assessed by real-time polymerase chain reaction to determine the knock-down efficiency. Two days after the transfection, the percentage of apoptotic cells and the proportion of cells in cell cycle phases were compared between the treatment and the control groups using flow cytometry. The resultant change in cell proliferation due to the knock-down was determined by MTT assay. RESULTS: Transfection with the TN-C CRISPR/Cas9 plasmid reduced TN-C levels in the cells by approximately 49% relative to the scrambled -control CRISPR/Cas9 transfected cells. This TN-C downregulation increased the percentage of cells in apoptosis and induced G1-phase arrest. The combined effect of apoptosis and cell cycle arrest led to a significant decrease in the number of cancer cells in the treatment group.CONCLUSION: Our successful preliminary study of a potential TNBC gene therapy based on TN-C genome editing by the CRISPR/Cas9 system led to significant decrease in TNBC cell numbers and it justifies the testing of this system in more advanced preclinical studies.

Purpose The aim of the study was to evaluate the clinical implication of multigene panel testing of beyond BRCA genes in Korean patients with BRCA1/2 mutation-negative breast cancer.Materials and Methods Between 2016 and 2019, a total of 700 BRCA1/2 mutation-negative breast cancer patients received comprehensive multigene panel testing and genetic counseling. Among them, 347 patients completed a questionnaire about cancer worry, genetic knowledge, and preference for the method of genetic tests during pre- and post-genetic test counseling. The frequency of pathogenic and likely pathogenic variants (PV/LPV) were analyzed.Results At least one PV/LPV of 26 genes was found in 76 out of 700 patients (10.9 %). The rate for PV/LPV was 3.4% for high-risk genes (17 PALB2, 6 TP53, and 1 PTEN). PV/LPVs of clinical actionable genes for breast cancer management, high-risk genes and other moderate-risk genes such as ATM, BARD1, BRIP, CHEK2, NF1, and RAD51D, were observed in 7.4%. Patients who completed the questionnaire showed decreased concerns about the risk of additional cancer development (average score, 4.21 to 3.94; p < 0.001), influence on mood (3.27 to 3.13; p < 0.001), influence on daily functioning (3.03 to 2.94; p=0.006); and increased knowledge about hereditary cancer syndrome (66.9 to 68.8; p=0.025) in post-test genetic counseling. High cancer worry scales (CWSs) were associated with age ≤ 40 years and the identification of PV/LPV. Low CWSs were related to the satisfaction of the counselee.Conclusion Comprehensive multigene panel test with genetic counseling is clinically applicable. It should be based on interpretable genetic information, consideration of potential psychological consequences, and proper preventive strategies.

Breast cancer is the most commonly diagnosed cancer worldwide and remains the second leading cause of cancer death. While breast cancer mortality has steadily declined over the past decades through medical advances, an alarming disparity in breast cancer mortality has emerged between African American women (AAW) and Caucasian American women (CAW); and new evidence suggests more aggressive behavior of triple-negative breast cancer (TNBC) in AAW may contribute to racial differences in tumor biology and mortality. Progesterone (PRG) is capable of exerting its cellular effects through either its classic, non-classic or combined responses through binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs), warranting both pathways an equally important status in PRG-mediated signaling. In our previous report, we demonstrated that the CCM signaling complex (CSC) consisting of CCM1, CCM2, and CCM3 proteins can couple both nPRs and mPRs signaling cascades to form a CSC-mPRs-PRG-nPRs (CmPn) signaling network in nPR positive(+) breast cancer cells. In this report, we furthered our research by establishing the CSC-mPRs-PRG (CmP) signaling network in nPR(-) breast cancer cells, demonstrating that a common core mechanism exists, regardless of nPR(+/-) cell type. This is the first report stating that inducible expression patterns exist between CCMs and major mPRs in TNBC cells. Furthermore, we firstly show mPRs in TNBC cells are localized in the nucleus and participate in nucleocytoplasmic shuttling in a coordinately synchronized fashion with CCM proteins under steroid actions, following the same cellular distribution as other well-defined steroid hormone receptors. Finally, for the first time, we deconvoluted the CmP signalosome by using multi-omics approaches, which helped us understand key factors within the CmP network, and identify 21 specific biomarkers with potential clinical applications associated with AAW-TNBC tumorigenesis. These novel biomarkers could have immediate clinical implications to dramatically improve health disparities among AAW-TNBCs.

Background: Triple Negative Breast Cancer (TNBC) commonly displays Epidermal growth factor receptor (EGFR). Effective EGFR degradation results in the suppression of tumor in various models. Studies have addressed the relevance of this strategy in the treatment of TNBC. In the present study, we examined the effect of 17 β- estradiol on EGFR expression in MDA-MB-231 (TNBC) cell line and assessed whether 17 β-estradiol degrades EGFR by ubiquitination pathway. Objectives: The objectives of this study are to treat MDA-MB-231 cell lines with Cycloheximide with or without 17β-estrdiol to observe whether 17β-estradiol leads to EGFR degradation and to treat with MG-132 to assess whether degradation occurs through ubiquitination pathway. Methods: MDA-MB-231 cells were treated with 17β-estradiol (E2) and EGFR expression was studied by western blotting at different intervals by using Cycloheximide chase. To assess ubiquitination pathway of degradation of EGFR in MDA-MB-231 cell line, MG-132 was used. Results: EGFR expression was reduced with β-estradiol treatment in MDA-MB-231 cell line with Cycloheximide chase. Upon Treatment with MG-132 and E2, EGFR expression did not reduce, suggesting that Estrogen degrades EGFR by ubiquitination pathway. Conclusion: Estrogen degrades EGFR in MDA-MB-231 cells and this degradation occurs by ubiquitination.

Background: Different molecular breast cancer subtypes present different biologic features, treatment options, and clinical prognoses. The breast cancer imaging phenotype may help precisely classify breast cancer in a non-invasive manner. Objective: To identify the association between the imaging and clinicopathologic features of invasive breast cancer according to the molecular subtype. Methods: We retrospectively reviewed the electronic medical records of 313 consecutive women with breast cancer who underwent surgery between March 2018 and February 2019. Preoperative imaging studies were also reviewed and the association between the clinicopathologic and imaging features was evaluated according to the molecular subtype. Results: On mammography, the presence of microcalcifications was correlated with the human epidermal factor receptor 2-positive subtype (67%, 14/21). Luminal A and B tumors were more likely to have a spiculated margin (57% [63/110] and 41% [34/81]), while human epidermal factor receptor 2-positive and triple-negative breast cancers were more likely to have an indistinct margin (56% [10/18] and 35% [17/48]). On ultrasonography, luminal A tumors were likely to be depicted as masses with an irregular shape (85%, 115/136) and spiculated margin (49%, 66/136). On magnetic resonance imaging, triple-negative breast cancer appeared as a mass (n=13) that frequently had an irregular shape (62%, 8/13) but was more likely to be oval or round (39%, 5/13) than other subtypes. Conclusion: Some imaging features on mammography, ultrasonography, and magnetic resonance imaging could be useful predictors of the molecular subtype of breast cancer and may aid precision medicine development for patients with breast cancer according to the subtype.

Background : Metabolic syndrome (MetS) is characterized by a cluster of biological irregularities. The purpose of this analysis was to examine the association of MetS with BC among Nigerian women, and for the first time evaluate this association by molecular subtype. Methods : MetS was defined as having at least 3 out of 5 of: high blood pressure (≥130/85 mm Hg), reduced HDL ( 150 mg/dL), high waist circumference (≥80 cm), and prior diagnosis of diabetes or elevated fasting glucose level (≥100 mg/dL). Among 296 newly diagnosed BC cases and 259 healthy controls, multivariable logistic regression models were utilized to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) for the association between MetS and BC overall. Multinomial logistic regression models were used to evaluate each molecular subtype (Luminal A, Luminal B, HER2-enriched and triple-negative or TNBC). Results : After adjusting for age, socio-demographic and reproductive risk factors, there was a positive association between MetS and BC (aOR: 1.84, 95% CI: 1.07, 3.16). In stratified analyses, MetS was associated with BC regardless of BMI status; however, the estimate was significant only among normal weight women (aOR: 3.85; 95% CI: 1.25, 11.90). MetS was significantly associated with TNBC subtype (aOR: 4.37, 95% CI: 1.67, 11.44); associations for other molecular subtypes were not statistically significant. Conclusion : MetS appears to be a robust risk factor for BC, particularly for TNBC. Public health and clinical interventions can provide substantial benefits in reducing the burden of MetS and preventing BC among Nigerian women. MICRO-ABSTRACT : Metabolic syndrome is a cluster of biological irregularities that is a known risk factor for cardiovascular disease, stroke, and diabetes. In a case-control study of 555 Nigerian women, we observed that metabolic syndrome was strongly associated with breast cancer and the aggressive triple-negative molecular subtype, highlighting a need for clinical and lifestyle interventions targeting metabolic syndrome to reduce breast cancer risk in this population.

BACKGROUND: Breast cancer (BC) is one of the most life-threatening cancer types among women. Despite major developments in medical sciences and technologies, the incidence and mortality rates of BC cases are still increasing. One of the reasons for this increase is the absence of an easy to perform early-diagnostic tool. Although there are defined BC biomarkers routinely used for diagnostic and prognostic purposes, none of these biomarkers is useful for early diagnosis. Therefore, early diagnosis of BC remains an important challenge and there is a great need for the early-diagnostic biomarker(s). OBJECTIVE: In this study, we aimed to evaluate the diagnostic and prognostic values of glycerol-3-phosphate dehydrogenase (GPD1) and monoacylglycerol lipase (MAGL) proteins as non-invasive serum biomarkers. METHODS: GPD1 and MAGL serum levels were determined by ELISA for BC patients (n= 100) from five different subtypes, and healthy controls (n= 20), and a comparative analysis was performed to determine statistically significant expression differences among the groups. RESULTS: The results provided evidence that GPD1 acted as a diagnostic biomarker in distinguishing triple-negative breast cancer (TNBC) patients from other subtypes, and MAGL acted as a diagnostic biomarker in distinguishing healthy individuals from BC patients. CONCLUSION: GPD1 and MAGL might be proposed as non-invasive diagnostic biomarkers for BC with high sensitivity and specificity.

Purpose This study aimed to investigate the impact of postoperative radiotherapy (PORT) in de novo metastatic breast cancer (dnMBC) patients undergoing planned primary tumor resection (PTR) and to identify the subgroup of patients who would most benefit from PORT.Materials and Methods This study enrolled 426 patients with dnMBC administered PTR alone or with PORT. The primary and secondary outcomes were overall and progression-free survival (OS and PFS), respectively.Results The median follow-up time was 53.7 months (range, 3.1 to 194.4). The 5-year OS and PFS rates were 73.2% and 32.0%, respectively. For OS, clinical T3/4 category, triple-negative breast cancer (TNBC), postoperative chemotherapy alone were significantly poor prognostic factors, and administration of PORT failed to show its significance. Regarding PFS, PORT was a favorable prognostic factor (hazard ratio, 0.64; 95% confidence interval, 0.50 to 0.82; p < 0.001), in addition to T1/2 category, ≤ 5 metastases, and non-TNBC. According to the multivariate analyses of OS in the PORT group, we divided the patients into three groups (group 1, T1/2 and non-TNBC [n=193]; group 2, T3/4 and non-TNBC [n=171]; and group 3, TNBC [n=49]), and evaluated the effect of PORT. Although PORT had no significance for OS in all subgroups, it was a significant factor for good prognosis regarding PFS in groups 1 and 2, not in group 3.Conclusion PORT was associated with a significantly better PFS in patients with dnMBC who underwent PTR. Patients with clinical T1/2 category and non-TNBC benefited most from PORT, while those with TNBC showed little benefit.

Background: Triple Negative Breast Cancer (TNBC) is considered as the most deadly subtype of breast cancer, because of heterogeneity, less treatment options and resistance to chemotherapy. Objective: To find out an efficient chemotherapeutic options, in this study we have investigated the combined therapy of 5-Fluorouracil (5-FU) and thymoquinone (TQ) against TNBC cell lines BT-549 and MDA-MB-231. Methods: We have tested 5-FU and TQ alone and in combination (5-FU + TQ) to observe the cellular growth, cell cycle and apoptosis status of BT-549 and MDA-MB-231 cells. Also we have measured the mRNA level expression of genes related to cell cycle and apoptosis. Results: Experimental results suggest that both of 5-FU and TQ are effective in controlling cell growth, cell cycle and inducing apoptosis, but their combination is much more effective. 5-FU was found to be more effective in controlling cell growth, while TQ was found to be more effective in inducing apoptosis, but in both cases, their combination was most effective. TQ was found more effective in increasing and BAX/BCL-2 ratio, while 5-FU was more effective in inhibiting thymidylate synthase. They showed significant increasing effects on caspases and P53 and decreasing effect on CDK-2, where their combination was found most effective. Conclusions: Thus, TQ and 5-FU probably showed synergistic effect on both of cell cycle and apoptosis of tested TNBC cell lines. Our study reveals that TQ can synergise 5-FU action, and increase its anticancer efficiency against TNBC cells, which might be good choice in drug development for TNBC treatment.

Purpose: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Patients with early-stage TNBCs have distinct likelihood of distant recurrence. Current therapeutic guidance is still limited.Methods: We extracted transcriptome data for 189 pathologically confirmed pT1-2N0M0 TNBC patients at Fudan University Shanghai Cancer Center. Candidate mRNAs were filtered, which was followed by differential expressed mRNAs analysis, survival analysis, and LASSO Cox regression model. All-subsets regression program was used for constructing a multi-mRNA signature in the training set (n=159); the accuracy and prognostic value were then validated using an independent validation set (n=158). Results: Here, we profiled the transcriptome data from 189 early-stage TNBC patients along with 50 paired normal tissues. Early-stage TNBCs are featured of basal-like and immune-suppressed subtype and homologous recombination ability deficiency. We developed a prognostic signature contained seven mRNAs from transcriptome data (ACAN, KRT5, TMEM101, LCA5, RPP40, LAGE3, CDKL2). In both the training (n=159) and validation cohorts (n=158), the signature could identify patients with relatively high recurrence risks and serve as an independent prognostic factor. The signature had better prognostic value than traditional clinicopathological features in both sets. Among the seven mRNAs, TMEM101 is highly expressed in TNBC and represents a potential therapeutic target. Inhibition of TMEM101 impaired tumor progression.Conclusions: Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. Clinical and genomic low risk TNBC patients may have the opportunity to avoid adjuvant chemotherapy

Purpose Questions remain about whether moderately hypofractionated whole-breast irradiation is appropriate for patients with triple-negative breast cancer. Methods and Materials Using the prospective database of a multicenter, collaborative quality improvement consortium, we identified patients with node-negative, triple-negative breast cancer who received whole-breast irradiation with either moderate hypofractionation or conventional fractionation. Using inverse probability of treatment weighting (IPTW), we compared outcomes using the Kaplan-Meier product-limit estimation method with Cox regression models estimating the hazard ratio for time-to-event endpoints between groups. Results The sample included 538 patients treated at 18 centers in 1 state in the United States, of whom 307 received conventionally fractionated whole-breast irradiation and 231 received moderately hypofractionated whole-breast irradiation. The median follow-up time was 5.0 years (95% confidence interval [CI], 4.77-5.15 years). The 5-year IPTW estimates for freedom from local recurrence were 93.6% (95% CI, 87.8%-96.7%) in the moderate hypofractionation group and 94.4% (95% CI, 90.3%-96.8%) in the conventional fractionation group. The hazard ratio was 1.05 (95% CI, 0.51-2.17; P = .89). The 5-year IPTW estimates for recurrence-free survival were 87.8% (95% CI, 81.0%-92.4%) in the moderate hypofractionation group and 88.4% (95% CI 83.2%-92.1%) in the conventional fractionation group. The hazard ratio was 1.02 (95% CI, 0.62-1.67; P = .95). The 5-year IPTW estimates for overall survival were 96.6% (95% CI, 92.0%-98.5%) in the moderate hypofractionation group and 93.4% (95% CI, 88.7%-96.1%) in the conventional fractionation group. The hazard ratio was 0.65 (95% CI, 0.30-1.42; P = .28). Conclusions Analysis of outcomes in this large observational cohort of patients with triple-negative, node-negative breast cancer treated with whole-breast irradiation revealed no differences by dose fractionation. This adds evidence to support the use of moderate hypofractionation in patients with triple-negative disease.

Triple-negative breast cancer (TNBC) is a highly resistant, lethal, and metastatic sub-division of breast carcinoma, characterized by the deficiency of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In women, TNBC shows a higher aggressive behavior with poor patient prognosis and a higher recurrence rate during reproductive age. TNBC is defined by the presence of epithelial- to-mesenchymal-transition (EMT), which shows a significant role in cancer progression. At the epigenetic level, TNBC is characterized by epigenetic signatures, such as DNA methylation, histone remodeling, and a host of miRNA, MiR-193, LncRNA, HIF- 2α, eEF2K, LIN9/NEK2, IMP3, LISCH7/TGF-β1, GD3s, KLK12, mediated regulation. These modifications either are silenced or activate the necessary genes that are prevalent in TNBC. The review is based on epigenetic mediated mechanistic changes in TNBC. Furthermore, Thymoquinone (TQ), Regorafenib, Fangjihuangqi decoction, Saikosaponin A, and Huaier, etc., are potent antitumor natural compounds extensively reported in the literature. Further, the review emphasizes the role of these natural compounds in TNBC and their possible epigenetic targets, which can be utilized as a potential therapeutic strategy in the treatment of TNBC.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, highlighting the unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDO) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBC). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven, basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, this study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and tailored treatment options. Significance: A comprehensive analysis of patient-derived organoids of TNBC provides insights into cellular heterogeneity and mechanisms of tumorigenesis at the single-cell level.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly malignant breast cancer subtype with a poor prognosis. The cell cycle regulator cyclin A2 (CCNA2) plays a role in tumor development. Herein, we explored the role of CCNA2 in TNBC. METHODS: We analyzed CCNA2 expression in 15 pairs of TNBC and adjacent tissues and assessed the relationship between CCNA2 expression using the tissue microarray cohort. Furthermore, we used two TNBC cohort datasets to analyze the correlation between CCNA2 and E2F transcription factor 1 (E2F1) and a luciferase reporter to explore their association. Through rescue experiments, we analyzed the effects of E2F1 knockdown on CCNA2 expression and cellular behavior. RESULTS: We found that CCNA2 expression in TNBC was significantly higher than that in adjacent tissues with similar observations in MDA-MB-231 and MDA-MB-468 cells. E2F1 was highly correlated with CCNA2 as observed through bioinformatics analysis (R= 0.80, P< 0.001) and through TNBC tissue verification analysis (R= 0.53, P< 0.001). We determined that E2F1 binds the +677 position within the CCNA2 promoter. Moreover, CCNA2 overexpression increased cell proliferation, invasion, and migration owing to E2F1 upregulation in TNBC. CONCLUSION: Our data indicate that E2F1 promotes TNBC proliferation and invasion by upregulating CCNA2 expression. E2F1 and CCNA2 are potential candidates that may be targeted for effective TNBC treatment.

Purpose Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. MethodsA total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical pathologic characteristics, survival and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. Results The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years-old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, pBRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. ConclusionOur study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

Background:Among all the types of breast cancer (BC), triple negative breast cancer (TNBC) is the most aggressive form having high metastasis and recurrence rate with limited treatment options. Conventional treatments such as chemotherapy and radiotherapy have lots of toxic side effects and also no FDA approved therapies are available till now. Repurposing of old clinically approved drugs towards various targets of TNBC is the new approach with lesser side effects and also leads to successful inexpensive drug development with less time consuming. Medicinal plants containg various phytoconstituents (flavonoids, alkaloids, phenols, essential oils, tanins, glycosides, lactones) plays very crucial role in combating various types of diseases and used in drug development process because of having lesser side effects.Objective:The present review focuses in summarization of various categories of repurposed drugs against multitarget of TNBC and also summarizes the phytochemical categories that targets TNBC singly or in combination with synthetic old drugs.Methods:Literature information was collected from various databases such as Pubmed, Web of Science, Scopus and Medline to understand and clarify the role and mechanism of repurposed synthetic drugs and phytoconstituents aginst TNBC by using keywords like “breast cancer”, “repurposed drugs”, “TNBC” and “phytoconstituents”.Results:Various repurposed drugs and phytochemicals targeting different signaling pathways that exerts their cytotoxic activities on TNBC cells ultimately leads to apoptosis of cells and also lowers the recurrence rate and stops the metastasis process.Conclusion:Inhibitory effects seen in different levels, which provides information and evidences to researchers towards drug developments process and thus further more investigations and researches need to be taken to get the better therapeutic treatment options against TNBC.

Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung-resident fibroblasts to produce the C-C motif chemokines 2/7 (CCL2/7), which, in turn, activate cholesterol synthesis in lung-colonizing TNBC cells and induce angiogenesis at lung metastatic sites. Inhibiting cholesterol synthesis in lung-colonizing breast tumor cells by pulmonary administration of simvastatin-carrying HER3-targeting nanoparticles reduces angiogenesis and growth of lung metastases in a syngeneic TNBC mouse model. Our findings reveal a novel, chemokine-regulated mechanism for the cholesterol synthesis pathway and a critical role of metastatic site-specific cholesterol synthesis in the pulmonary tropism of TNBC metastasis. The study has implications for the unresolved epidemiological observation that use of cholesterol-lowering drugs has no effect on breast cancer incidence but can unexpectedly reduce breast cancer mortality, suggesting interventions of cholesterol synthesis in lung metastases as an effective treatment to improve survival in individuals with TNBC.

Introduction Triple-negative breast cancer (TNBC) in men is very rare. The clinical characteristics, prognostic factors, and overall survival of men with TNBC have not been characterized. Methods The study population consisted of men and women with a diagnosis of stage I-III TNBC between 2010 and 2016 in the National Cancer Database. Baseline demographic and tumor characteristics between men and women were compared using Pearson's Chi-Square test for categorical variables and Mann-Whitney U test for continuous variables. Kaplan–Meier and multivariate Cox proportional hazards regression model was used to compare survival and identify prognostic factors. Results A total of 311 men and 95,406 women with TNBC were included in the final analysis. The 3-year and 5-year overall survival was 74.8% and 68.8% in men, while it was 83.2% and 74.8% in women, respectively. In multivariate analysis, men were found to have a significantly worse overall survival compared to women (HR, 1.49, 95% CI, 1.19-1.86, P= .01). Older age at diagnosis, higher TNM stage, undergoing mastectomy and not undergoing chemotherapy or radiation were identified as independent negative prognostic factors in men with TNBC. Conclusion In one of the largest studies of men with TNBC, men were noted to have a poorer overall survival compared to women, despite adjusting for usual prognostic factors. Further research into differences in tumor biology, treatment patterns and compliance with therapy between men and women are needed to understand the underlying etiologies for the survival difference in TNBC.

Background: Transforming growth factor (TGF-β) pathway mediates suppression of anti-tumor immunity, and is associated with poor prognosis in triple-negative breast cancer (TNBC). Methods: In this study, we generated a humanized animal model by transplanting human peripheral blood mononuclear cells into immunodeficient mice followed by inoculation of MDA-MB-231 cells, and subsequently analyzed the role of TGF-β2 in the interaction between human T cells and human tumor cells. Results: Following reconstitution of the human immune system, inhibition of TGF-β signaling by TGF-β2 antisense oligodeoxynucleotide (TASO) resulted in accelerated tumor growth inhibition. TGF-β2 inhibition also resulted in downregulation of peripheral Foxp3+ regulatory T cells (Treg), whereas no effect was seen in the expression of CD8+ cytotoxic T cells. Analysis of the TASO-treated mice serum revealed elevated levels of human IFN-γ and reduced levels of human IL-10 and TGF-β2. Moreover, TGF-β2 inhibition resulted in increased CD8+ T cell infiltration, whereas the reduced infiltration of Tregs into the tumor partly resulted from decreased expression of CCL22. Decreased intra-tumoral Tregs facilitated the activation of cytotoxic T cells, associated with increased granzyme B expression. Conclusion: These results indicate that TASO potentiated T-cell mediated antitumor immunity, and it is proposed that TGF-β2 may be a promising target in the immunotherapeutic strategy of TNBC.

Basal-like breast cancer is the most aggressive breast cancer subtype with the worst prognosis. Despite its high recurrence rate, chemotherapy is the only treatment for basal-like breast cancer, which lacks expression of hormone receptors. In contrast, luminal A tumors express ERα and can undergo endocrine therapy for treatment. Previous studies have tried to develop effective treatments for basal-like patients using various therapeutics but failed due to the complex and dynamic nature of the disease. In this study, we performed a transcriptomic analysis of patients with breast cancer to construct a simplified but essential molecular regulatory network model. Network control analysis identified potential targets and elucidated the underlying mechanisms of reprogramming basal-like cancer cells into luminal A cells. Inhibition of BCL11A and HDAC1/2 effectively drove basal-like cells to transition to luminal A cells and increased ERα expression, leading to increased tamoxifen sensitivity. High expression of BCL11A and HDAC1/2 correlated with poor prognosis in patients with breast cancer. These findings identify mechanisms regulating breast cancer phenotypes and suggest the potential to reprogram basal-like breast cancer cells to enhance their targetability. Significance: A network model enables investigation of mechanisms regulating the basal-to-luminal transition in breast cancer, identifying BCL11A and HDAC1/2 as optimal targets that can induce basal-like breast cancer reprogramming and endocrine therapy sensitivity.

The protein-coding ability of circular RNAs (circRNAs) has recently been a hot topic, but the expression and roles of protein-coding circRNAs in triple-negative breast cancer (TNBC) remain uncertain. By intersecting circRNA sequencing data from clinical samples and cell lines, we identified a circRNA, termed circ-EIF6, which predicted a poorer prognosis and correlated with clinicopathological characteristics in a cohort of TNBC patients. Functionally, we showed that circ-EIF6 promoted the proliferation and metastasis of TNBC cells in vitro and in vivo. Mechanistically, we found that circ-EIF6 contains a 675-nucleotide (nt) open reading frame (ORF) and that the -150-bp sequence from ATG functioned as an internal ribosome entry site (IRES), which is required for translation initiation in 5' cap-independent coding RNAs. circ-EIF6 encodes a novel peptide, termed EIF6-224 amino acid (aa), which is responsible for the oncogenic effects of circ-EIF6. The endogenous expression of EIF6-224aa was further examined in TNBC cells and tissues by specific antibody. Moreover, EIF6-224aa directly interacted with MYH9, an oncogene in breast cancer, and decreased MYH9 degradation by inhibiting the ubiquitin-proteasome pathway and subsequently activating the Wnt/beta-catenin pathway. Our study provided novel insights into the roles of protein-coding circRNAs and supported circ-EIF6/EIF6-224aa as a novel promising prognostic and therapeutic target for tailored therapy in TNBC patients.

Background:The NCI requires designated cancer centers to conduct catchment area assessments to guide cancer control and prevention efforts designed to reduce the local cancer burden. We extended and adapted this approach to a community cancer center catchment area with elevated rates of triple-negative breast cancer (TNBC).Methods:Cancer registry data for 462 TNBC and 2,987 “Not-TNBC” cases diagnosed between 2012 and 2020 at the Helen F. Graham Cancer Center & Research Institute (HFGCCRI), located in New Castle County, Delaware, were geocoded to detect areas of elevated risk (hot spots) and decreased risk (cold spots). Next, electronic health record (EHR) data on obesity and alcohol use disorder (AUD) and catchment area measures of fast-food and alcohol retailers were used to assess for spatial relationships between TNBC hot spots and potentially modifiable risk factors.Results:Two hot and two cold spots were identified for TNBC within the catchment area. The hot spots accounted for 11% of the catchment area but nearly a third of all TNBC cases. Higher rates of unhealthy alcohol use and obesity were observed within the hot spots.Conclusions:The use of spatial methods to analyze cancer registry and other secondary data sources can inform cancer control and prevention efforts within community cancer center catchment areas, where limited resources can preclude the collection of new primary data.Impact:Targeting community outreach and engagement activities to TNBC hot spots offers the potential to reduce the population-level burden of cancer efficiently and equitably.

INTRODUCTION: Neoadjuvant systemic therapy (NST) is increasingly applied in breast cancer to improve surgical and oncological outcome. Approximately 21% of patients receiving NST achieve pathological complete response (pCR) of the breast. There is disagreement on the definition of pCR with respect to residual DCIS (ypT0 versus ypT0/is). The aim of this retrospective study was to determine the percentage of breast pCR (ypT0) and residual DCIS (ypTis), and its association with clinicopathological variables, in patients treated with NST and surgery.MATERIALS AND METHODS: Patients with invasive breast cancer treated with neoadjuvant chemotherapy, with or without targeted therapy, in the period of 2010-2019 were selected from the Netherlands Cancer Registry (NCR). Descriptive statistics and multivariable logistic regression analyses were used to analyse the percentage of ypT0 and ypTis and its association with clinicopathological variables.RESULTS: From the NCR database, 20495 patients were included, of whom 5847 (28.5%) achieved breast pCR (ypT0) and 881 (4.3%) showed residual DCIS (ypTis). The percentage of ypTis was highest in HER2+ tumour subtypes (ER+HER2+ 7.9%, ER-HER2+ 9.8%, ER+HER2- 2.1%, triple negative 3.3%, p < 0.001). Multivariable logistic regression analyses demonstrated high tumour grade (OR 2.00, p = 0.003) and HER2+ tumour subtype (ER+HER2+ OR 3.58, ER-HER2+ OR 4.37, p < 0.001) as independent predictors for ypTis.CONCLUSION: pCR (ypT0) was achieved in 5847 (28.5%) patients receiving NST and residual DCIS (ypTis) was found in 881 (4.3%) patients. Consequently, the rate of pCR may be affected by ypTis when not excluded from the definition. The percentage of ypTis is highest in HER2+ subtypes.

AIM To prepare the hyaluronic acid-coated Olaparib-loaded PEI - PLGA nanoparticles (HA-Ola-PPNPs) and investigate their tumor-targeted anticancer effect. METHODS The synthesis of HA-Ola-PPNPs was verified by DLS, TEM and SEM, followed was measured its cytotoxicity using CCK-8 assay. Confocal microscopy was used to observe the cellular uptake. Cell apoptosis was analyzed by flow cytometry, biological SEM and TEM. The expression of related proteins within the tumor site was investigated by immunostaining. RESULTS The prepared HA-Ola-PPNPs showed diameter of ∼160 nm with negatively charged surface (-16.9 ± 2.7 mV) and sustained drug release behavior. And the encapsulation efficiency of HA-Ola-PPNPs was 78.63 ± 5.29%. HA-Ola-PPNPs exhibited efficient in vitro and in vivo antitumor activities. HA-Ola-PPNPs induced cell apoptosis by upregulating Bax, Cytochrome C and Caspase 3, downregulating Bcl-2 in breast cancer-bearing mice. CONCLUSIONS According to the results, the Ola-loaded and HA-coated PEI - PLGA nanoparticles could be considered as a powerful tumor-targeted drug delivery system for TNBC treatment.

Background: Androgens potentially have an important role in the biology of breast cancer, particularly triple-negative breast cancer (TNBC). Androgen receptor (AR) may offer a novel therapeutic strategy, including the use of microRNA (miRNA) molecules. We have previously shown that AR agonist, dihydrotestosterone (DHT), increases the expression of miR-328-3p in the TNBC MDA-MB-231 cells. One target of the latter miRNA is ATP-binding cassette subfamily G member 2 (ABCG2), which modulates the chemo-response of cancer cells by pumping out xenobiotics. Objective: Using MDA-MB-231 cells as a model system for TNBC, we hypothesized that DHT would induce cell sensitivity towards doxorubicin via increasing levels of miR-328-3p and, consequently, reducing ABCG2 levels. Methods: Chemo-response of cells towards doxorubicin, tamoxifen, and mitoxantrone was evaluated using cell viability MTT assay. Cells were transfected with both miR-328-3p mimic or antisense molecules. Real-time PCR was utilized to assess RNA levels and immunoblotting was performed to investigate levels of ABCG2 protein. PCR arrays were used to assess changes in the expression of drug response regulatory genes. Results: Contrary to our hypothesis, treating MDA-MB-231 cells with DHT no effect towards tamoxifen or mitoxantrone, increased cell resistance towards doxorubicin was noted, concomitant with decreased expression of ABCG2. This under-expression of ABCG2 was also found in MCF-7 and MDA-MB-453 cells treated with DHT. Although miR-328-3p decreased ABCG2 mRNA and protein levels, the miRNA did not alter the chemo-response of cells towards doxorubicin and did not affect DHT-induced chemo-resistance. AR activation slightly decreased the expression of 5 genes, including insulin-like growth factor 1 receptor that may explain the mechanism of DHT-induced chemo-resistance of cells. Conclusion: DHT regulates chemo-response via a mechanism independent of ABCG2 and miR-328-3p.

PURPOSE This guideline updates recommendations of the ASCO guideline on chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2–negative metastatic breast cancer (MBC) that is either endocrine-pretreated or hormone receptor (HR)–negative. METHODS An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. RESULTS The Expert Panel reviewed abstracts from the literature review and retained 14 articles. RECOMMENDATIONS Patients with triple-negative, programmed cell death ligand-1–positive MBC may be offered the addition of immune checkpoint inhibitor to chemotherapy as first-line therapy. Patients with triple-negative, programmed cell death ligand-1–negative MBC should be offered single-agent chemotherapy rather than combination chemotherapy as first-line treatment, although combination regimens may be offered for life-threatening disease. Patients with triple-negative MBC who have received at least two prior therapies for MBC should be offered treatment with sacituzumab govitecan. Patients with triple-negative MBC with germline BRCA mutations previously treated with chemotherapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. Patients with HR-positive human epidermal growth factor receptor 2–negative MBC for whom chemotherapy is being considered should be offered single–agent chemotherapy rather than combination chemotherapy, although combination regimens may be offered for highly symptomatic or life-threatening disease. Patients with HR-positive MBC with disease progression on an endocrine agent may be offered treatment with either endocrine therapy with or without targeted therapy or single-agent chemotherapy. Patients with HR-positive MBC with germline BRCA mutations no longer benefiting from endocrine therapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. No recommendation regarding when a patient's care should be transitioned to hospice or best supportive care alone is possible. Additional information is available at www.asco.org/breast-cancer-guidelines .

DDB1 and CUL4 associated factor 13 (DCAF13) is a substrate receptor in the CUL4‐DDB1 E3 ligase, and its expression is associated with the prognosis of certain cancers. In the present study, we report evidence that DCAF13 is aberrantly overexpressed in human breast cancer and its expression is positively associated with cancer progression. Further analysis showed that the DCAF13 expression level is significantly higher in triple‐negative breast cancer compared to non‐triple‐negative breast cancer, indicating a positive correlation between its expression and the aggressiveness of breast cancer. Subsequent studies revealed that DCAF13 regulates cancer cell migration, invasion and epithelial–mesenchymal transition in human breast cancer, whereas it has no significant impact on breast cancer cell proliferation, cell cycle progressionor apoptosis. Taken together, our results demonstrate that DCAF13 promotes the epithelial–mesenchymal transition in human breast cancer cells, indicating an involvement in breast cancer metastasis. Furthermore, we report that doxorubicin, a widely used chemotherapy drug, increases DCAF13 expression in breast cancer cells, leading to enhanced cancer cell migration and invasion. These results suggest that doxorubicin chemotherapy may increase the risk of metastasis of drug‐resistant breast cancer cells, and future therapeutics targeting DCAF13 may help reduce the risk, especially for patients undergoing chemotherapy., DCAF13 is a substrate receptor in the CUL4‐DDB1 E3 ligase. We report that doxorubicin, a widely used chemotherapy drug, increases DCAF13 expression in breast cancer cells, leading to enhanced cancer cell migration and invasion, suggesting that doxorubicin may increase the risk of metastasis of drug‐resistant breast cancer cells, and future therapeutics targeting DCAF13 may help reduce the risk.

Breast cancer (BC) treatment frequently involves microtubule-targeting agents (MTAs), such as paclitaxel, that arrest cells in mitosis. Sensitivity to MTAs is defined by a subset of pro- and anti-apoptotic BCL2 family proteins controlling mitochondrial apoptosis. Here, we aimed to determine their prognostic value in primary tumour samples from 92 BC patients. Our analysis identified high NOXA/PMAIP mRNA expression levels as an independent prognostic marker for improved relapse-free survival (RFS) and overall survival (OS) in multivariate analysis in BC patients, independent of their molecular subtype. Analysis of available TCGA datasets of 1060 BC patients confirmed our results and added a clear predictive value of NOXA mRNA levels for patients who received MTA-based therapy. In this TCGA cohort, 122 patients received MTA-treatment and high NOXA mRNA levels correlated with their progression-free interval (PFI) and OS. Our follow-up analyses in a panel of BC cell lines of different molecular subtypes identified NOXA protein expression as a key determinant of paclitaxel sensitivity in triple-negative breast cancer (TNBC) cells. Moreover, we noted highest additive effects between paclitaxel and chemical inhibition of BCLX, but not BCL2 or MCL1, documenting dependence of TNBC cells on BCLX for survival and paclitaxel sensitivity, defined by NOXA expression levels.

Triple negative breast cancer represents multiple genomic and transcriptomic heterogeneities. Genetic and epigenetic changes emerging in TNBC help it in acquiring resistance against immunological response. Distant metastasis, lack of clinically targeted therapies and prognostic markers make it the most aggressive form of breast cancer. In this review, we showed that driver alterations in targeted genes AR, ERR, TIL, TAM, miRNA, mTOR and immunosuppressive cytokines are predominantly involved in complicating TNBC by inducing cell proliferation, invasion and metastasis, and by inhibiting apoptosis. The role of node status, cathepsin-D, Ki-67 index, CD3+TIL, BRCA1 promoter methylation value and p53 as an efficient prognostic factor have also been studied to predict the disease free and overall survival rate in TNBC patients. The present review article is an attempt to gain an insight with a new vision on the etiology of TNBC, its treatment strategies and prognostic marker to identify the outcome of standard therapies and to re-design future treatment strategies to provide maximum benefit to patients.

PURPOSE There are sparse data on the outcome of patients with locally advanced breast cancer (LABC). This report is on the prognostic factors and long-term outcome from Cancer Institute, Chennai. METHODS This is an analysis of untreated patients with LABC (stages IIIA-C) who were treated from January 2006 to December 2013. RESULTS Of the 4,577 patients with breast cancer who were treated, 2,137 patients (47%) with LABC were included for analysis. The median follow-up was 75 months (range, 1-170 months), and 2.3% (n = 49) were lost to follow-up at 5 years. The initial treatment was neoadjuvant concurrent chemoradiation (NACR) (77%), neoadjuvant chemotherapy (15%), or others (8%). Patients with triple-negative breast cancer had a pathologic complete response (PCR) of 41%. The 10-year overall survival was for stage IIIA (65.1%), stage IIIB (41.2%), and stage IIIC (26.7%). Recurrence of cancer was observed in 27% of patients (local 13% and distant 87%). Multivariate analysis showed that patients with a tumor size > 10 cm (hazard ratio [HR], 2.19; 95% CI, 1.62 to 2.98; P = .001), hormone receptor negativity (HR, 1.45; 95% CI, 1.22 to 1.72; P = .001), treatment modality (neoadjuvant chemotherapy, HR, 0.56; 95% CI, 0.43 to 0.73; P = .001), lack of PCR (HR, 2.36; 95% CI, 1.85 to 3.02; P = .001), and the presence of lymphovascular invasion (HR, 1.97; 95% CI, 1.60 to 2.44; P = .001) had decreased overall survival. CONCLUSION NACR was feasible in inoperable LABC and gave satisfactory long-term survival. PCR was significantly higher in patients with triple-negative breast cancer. The tumor size > 10 cm was significantly associated with inferior survival. However, this report acknowledges the limitations inherent in experience of management of LABC from a single center.

Background Pristimerin, a natural flavonoid compound, has potential anti-tumor activities. These activities have been illustrated in various cancer cell lines, including MDA-MB-231 cells. MDA-MB-231 cells are a representative mesenchymal subtype of triple negative breast cancer (MES-TNBC) cell line. Currently, the main treatment for patients with advanced MES-TNBC is cytotoxic chemotherapy. We tried to examine the role and effect of pristimerin on epithelial–-mesenchymal transition (EMT) in MDA-MB-231 cells. Material and methods The effects of pristimerin on the proliferation of MDA-MB-231 cells were investigated by cloning formation growth assay. In vitro transwell and adhesion assays were performed for cell invasion and adhesion. The expression levels of EMT markers in E-cadherin and N-cadherin were examined by western blotting. We also established overexpressed- and silenced-integrin β3 cell lines to evaluate the role of integrin β3 in mediating the EMT reversion events in MDA-MB-231 cells. Results Pristimerin inhibited cell proliferation, and its inhibitory effect was dose-dependent. We demonstrated that pristimerin reserved EMT by upregulating E-cadherin and downregulating N-cadherin expression. Meanwhile, we revealed that pristimerin inhibited mRNA and protein expression of integrin β3, which is a key heterodimeric transmembrane receptor associated with EMT. These inhibitory effects and reversion of EMT were enhanced when integrin β3 was knockdown in MDA-MB-231 cells, while the overexpression of integrin β3 attenuated these effects. In vivo studies using xenograft mouse model demonstrated that pristimerin inhibited tumor growth. Conclusions Our findings provide important insights into the effects of pristimerin on inhibiting cancer progression and EMT reversion by suppression of integrin β3.

Different immunohistochemical programmed death-ligand 1 (PD-L1) assays and scorings have been reported to yield variable results in triple-negative breast cancer (TNBC). We compared the analytical concordance and reproducibility of four clinically relevant PD-L1 assays assessing immune cell (IC) score, tumor proportion score (TPS), and combined positive score (CPS) in TNBC. Primary TNBC resection specimens (n = 104) were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3, and DAKO 28–8. PD-L1 expression was scored according to guidelines on virtual whole slide images by four trained readers. The mean PD-L1 positivity at IC-score ≥1% and CPS ≥1 ranged between 53% and 75% with the highest positivity for SP263 and comparable levels for 22C3, 28–8, and SP142. Inter-assay agreement was good between 28–8 and 22C3 across all scores and cut-offs (kappa 0.68–0.74) and for both assays with SP142 at IC-score ≥1% and CPS ≥1 (kappa 0.61–0.67). The agreement between SP263 and all other assays was substantially lower for all scores. Inter-reader agreement for each assay was good to excellent for IC-score ≥1% (kappa 0.73–0.78) and CPS ≥1 (kappa 0.68–0.74), fair to good for CPS ≥10 (kappa 0.52–0.67) and TPS ≥1% (kappa 0.53–0.72). The percentage of overlapping cases in the positive/negative category was >90% between IC-score ≥1% and CPS ≥1 but below when comparing IC-score ≥1% with CPS ≥10. We demonstrate an overall good inter-reader agreement for all PD-L1 assays in TNBC along with assay specific differences in positivity and concordances, which may aid to select the right test strategy in routine diagnostics., Highlights • Different PD-L1 IHC assays and scorings may show variable results in TNBC. • Overall good assay concordance between SP142, 22C3, and 28–8 at IC-score 1%. • Overall good assay concordance between SP142, 22C3, and 28–8 at CPS 1. • SP142 is less optimal for CPS assessment at higher cut-offs. • SP263 assay is not interchangeable with the other three PD-L1 assays.

Background: Triple-Negative Breast Cancer (TNBC) requires targeted therapies to better manage and prevent metastatic mammary gland tumors. Due to the resistance problem associated with the approved drugs, researchers are now focusing on phytochemicals for the treatment of TNBC as they possess pleiotropic mode of action and fewer side effects. Objective: To investigate the antiproliferative effect of citronellal on triple-negative breast cancer cells. Method: Anticancer potential of citronellal was explored by employing SRB, MTT, and NRU antiproliferative assay. Further, the effect of citronellal was observed on molecular targets (Tubulin, COX-2, and LOX-5) utilizing in vitro and in silico methods. Furthermore, the efficacy of citronellal was examined on Ehrlich Ascites Carcinoma cells. In addition, the safety profiling of it was observed at 300 and 1000 mg/kg of body weight in mice. Results: Citronellal suppresses the growth of MDA-MB-231 cells by more than 50% in NRU assay and ~41% and 32% in SRB and MTT assay, respectively. Further, citronellal's effect was observed on molecular targets wherein it suppressed LOX-5 activity (IC50 40.63±2.27 μM) and prevented polymerization of microtubule (IC50 63.62 μM). The result was more prominent against LOX-5 as supported by molecular docking interaction studies, but a non-significant effect was observed at the transcriptional level. The efficacy of citronellal was also determined in Ehrlich Ascites Carcinoma (EAC) model, wherein it inhibited the growth of tumor cells (45.97%) at 75 mg/kg of body weight. It was non-toxic up to 1000 mg/kg of body weight in mice and did not cause significant lysis of erythrocytes. Conclusion: These observations could provide experimental support for citronellal to be used as a chemopreventive agent for breast cancer.

Antibody-drug conjugates (ADCs) are among the most significant advances in clinical cancer treatments, however, they are haunted with fundamental issues like low drug/antibody ratio (DAR), need of large amount of antibody, and complex chemistry. Targeted nanomedicines while offering a promising alternative to ADCs are afflicted with drug leakage and inferior cancer-specificity. Herein, we developed an intelligent cell-selective nanotoxin based on anti-CD44 antibody-polymersome-DM1 conjugates (aCD44-AP-DM1) for potent treatment of solid tumors. DM1 was simultaneously coupled to vesicular membrane via disulfide bonds during self-assembly and anti-CD44 antibody was facilely clicked onto polymersome surface, tailor-making an optimal aCD44-AP-DM1 with a controlled antibody density of 5.0, extraordinary DAR of 275, zero drug leakage and rapid reduction-responsive DM1 release. aCD44-AP-DM1 displayed a high specificity and exceptional cytotoxicity toward MDA-MB-231 triple negative breast cancer, SMMC-7721 hepatocellular carcinoma and A549 non-small cell lung cancer cells with half-maximal inhibitory concentrations (IC50) of 21.4, 3.7 and 64.6 ng/mL, respectively, 3.6–47.2-fold exceeding non-targeted P-DM1. Intriguingly, the systemic administration of aCD44-AP-DM1 significantly suppressed subcutaneous MDA-MB-231 tumor xenografts in nude mice while intratumoral injection achieved complete tumor eradication in four out of five mice, without causing toxicity. This intelligent cell-selective nanotoxin has emerged as a better platform over ADCs for targeted cancer therapy.

PURPOSE Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) are determinants of treatment and mortality for patients with breast cancer (BC). In East Africa, the estimated 5-year survival (37.7%) is far lower than the US average (90%). This meta-analysis investigates BC receptor subtypes within five East African countries to ascertain cross-country patterns and prioritize treatment needs. METHODS From a PubMed search, January 1, 1998-June 30, 2019, for all English-only BC articles for Ethiopia, Kenya, Rwanda, Tanzania, and Uganda, eligible studies had receptor distributions for female BC samples ≥ 30 patients. Outcomes were proportions of ER+, PR+, and HER2-positive (HER2+), and/or molecular subtypes. Data included study characteristics and mean or median patient age. Using metaprop, Stata 16, we estimated pooled proportions (ES) with 95% CIs and assessed heterogeneity. RESULTS Among 36 BC studies with receptor data, 21 met criteria. Weighted mean age was 47.5 years and median, 48. Overall ES were as follows: 55% for ER-positive (ER+) (95% CI, 47 to 62), 23% for HER2+ (95% CI, 20 to 26), and 27% for triple-negative BC (TNBC) (95% CI, 23 to 32). CONCLUSION We found differences between countries, for example, lower distribution of TNBC in Ethiopia (21%) compared with Uganda (35%). ER+, the dominant BC subtype overall at 55%, emphasizes the need to prioritize endocrine therapy. Overall proportions of HER2+ BC (with or without ER+ or PR+), 23%, approached proportions of TNBC, 27%, yet HER2 testing and treatment were infrequent. Testing and reporting of receptor subtypes would promote delivery of more effective treatment reducing the mortality disparity.

Triple-negative breast cancer (TNBC) is the most aggressive subtype among breast cancers with high recurrence and this condition is partly due to chemoresistance. Therefore, fully understanding the mechanism of TNBC-resistance is the key to overcoming chemoresistance, which will be an effective strategy for TNBC therapy. Various potential mechanisms involved in the chemoresistance of TNBC have been investigated and indicated that noncoding RNAs (ncRNAs) especially microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) take part in most TNBC resistance. The ncRNA-induced chemoresistance process is involved in the alteration of many activities. here, we mainly summarize the mechanisms of ncRNAs in the chemoresistance of TNBC and discuss the potential clinical application of ncRNAs in the treatment of TNBC, indicating that targeting ncRNAs might be a promising strategy for resensitization to chemotherapies.

Evodiamine (Evo) is a quinazolinocarboline alkaloid found in Evodia rutaecarpa and exhibits moderate antiproliferative activity. Herein, we report using a scaffold-hopping approach to identify a series of novel polycyclic heterocyclic derivatives based on Evo as the topoisomerase I (Top1) inhibitor for the treatment of triple-negative breast cancer (TNBC), which is an aggressive subtype of breast cancer with limited treatment options. The most potent compound 7f inhibited cell growth in a human breast carcinoma cell line (MDA-MB-231) with an IC50 value of 0.36 μM. Further studies revealed that Top1 was the target of 7f, which directly induced irreversible Top1-DNA covalent complex formation or induced an oxidative DNA lesion through an indirect mechanism mediated by reactive oxygen species. More importantly, in vivo studies showed that 7f exhibited potent antitumor activity in a TNBC-patient-derived tumor xenograft model. These results suggest that compound 7f deserves further investigation as a promising candidate for the treatment of TNBC.

Background/aim Diallyl trisulfide (DATS) has been shown to prevent and inhibit breast carcinogenesis. CCL2/MCP-1 has been shown to play a significant role in breast cancer. This study explored DATS efficacy on triple-negative breast cancer (TNBC) cells. Materials and methods DATS efficacy on TNF-α induced TNBC cells were examined via trypan blue exclusion test, wound-healing assay, human cytokine arrays, ELISA, and RT-PCR. Results DATS significantly induced cell death and inhibited cell migration. Expression of CCL2/MCP-1, IL-6, PDGF-BB, NT-3, and GM-CSF in TNF-α-treated cells increased. However, DATS significantly decreased the expression of CCL2/MCP-1 in TNF-α-treated MDA-MB-231 but not in MDA-MB-468 cells. DATS significantly down-regulated mRNA expression of IKBKE and MAPK8 in both cell lines, indicating a possible effect in genes involved in the NF-κB and MAPK signaling. Conclusion DATS may have a role in TNBC therapy and prevention by targeting CCL2.

Background Matrix-producing breast carcinoma (MPBC) is a very rare and usually aggressive triple-negative breast cancer. We successfully established a patient-derived orthotopic xenograft (PDOX) model from a patient with MPBC and used it to study tumor sensitivity to various agents. Case report A 40-year-old woman was diagnosed with MPBC with a triple-negative phenotype. Due to axillary lymph-node metastases found during radical mastectomy, the patient was subsequently treated with epirubicin, cyclophosphamide and paclitaxel. In addition, radiotherapy was directed to the chest wall and subclavicular fossa. A portion of the cancer tissue from the mastectomy was used to establish a PDOX nude-mouse model. The PDOX model was resistant to paclitaxel, bevacizumab, vinorelbine, cisplatinum and olaparib, and sensitive to eribulin. Metastases in mediastinal lymph nodes and the right ovary were observed in the patient 14 months after mastectomy. Thoracoscopic mediastinal lymph-node biopsy and laparoscopic oophorectomy were performed, and both confirmed breast-cancer metastasis. The patient was then treated with paclitaxel and bevacizumab but no response was observed, which correlated with the inability of these drugs to arrest tumor growth in the PDOX models of the patient's tumor. The patient was then given eribulin based on the PDOX-model result, but treatment had to be stopped because of rapid progression of metastasis into the cervical lymph nodes and thyroid gland. The patient was subsequently treated with atezolizumab and nab-paclitaxel. Unfortunately, the patient died of her cancer 8 months after recurrence. Conclusion The present study demonstrates that the PDOX model of a patient's triple-negative MPBC accurately predicted that paclitaxel and bevacizumab would not arrest the patient's tumor growth. Eribulin may have been effective if administered at an earlier stage of the patient's cancer course. Drug-screening results from PDOX models should be used as early as possible in order to improve patient outcome.

Noncatalytic region of tyrosine kinase 1 (NCK1) plays a key role in extracellular matrix degradation, which is required for the metastasis of triple-negative breast cancer (TNBC). However, the role NCK1 plays in the metastatic progression of TNBC is unknown. Based on online databases, NCK1 was found to be highly expressed in TNBC as compared to normal breast-like subjects, which was also confirmed using TNBC cells and a tissue microarray. NCK1 expression gradually decreased with increased tumor stage. High NCK1 expression displayed a poor prognosis in lymph node-positive metastatic TNBC patients, but not in lymph node-negative patients. Using transwell assays and immunoblotting, we confirmed that NCK1 overexpression promoted, while NCK1 downregulation inhibited migration capabilities, as well as the expression of matrix metalloproteinases (MMP2/9), uridylyl phosphate adenosine, and plasminogen activator inhibitor-1 in TNBC cells. Mechanistically, NCK1 upregulation mediated the activation of MMP2/9 through ERK1/2 activity. Signal transducer and activator of transcription 3 (STAT3) was positively correlated with NCK1. STAT3 could directly bind to the promoter region of NCK1 to promote its expression and was accompanied by the elevation of MMP2/9 and ERK1/2 signaling, which were partially abolished by the knockdown of NCK1 in TNBC cells. NCK1 may serve as a diagnostic and prognostic marker of metastatic TNBC. STAT3 upregulation promoted the expression of NCK1, which subsequently induced the migration and activity of MMPs in a ERK1/2 signaling-dependent manner in TNBC cells. NCK1 is a promising target for improving TNBC migration.

Triple negative breast cancer (TNBC) is one of the leading causes of cancer death in the world and lacks an effective targeted therapy. G-protein-coupled receptor 161 (GPR161) has been demonstrated to perform the functional regulations on TNBC progression and might be a potential new target for TNBC therapy. This study showed the effects of bisdemethoxycurcumin (BDMC) on GPR161 regulation, indicating that BDMC effectively inhibited GPR161 expression and downregulated GPR161-driven signaling. BDMC showed the potent inhibitory effects on TNBC proliferation through suppressing GPR161-mediated mammalian target of rapamycin (mTOR)/70 kDa ribosomal protein S6 kinase (p70S6K) activation. Besides, in this study, we discover the mechanism of GPR161-driven TNBC metastasis, linking to GPR161-mediated twist-related protein 1 (Twist1)/matrix metallopeptidase 9 (MMP9) contributing to the epithelial-mesenchymal transition (EMT). BDMC effectively repressed GPR161-mediated TNBC metastasis via inhibiting Twist1/MMP9-induced EMT. The three-dimensional invasion assay also showed that BDMC significantly inhibited TNBC invasion. The combination treatment of BDMC and rapamycin enhanced the inhibition of TNBC proliferation and metastasis through increasing the blockage of mTOR activation. Furthermore, this study also observed that BDMC activated the caspase 3/9 signaling pathway to induce TNBC apoptosis. Therefore, BDMC could be applicable to anticancer therapy, especially targeting on the GPR161-driven cancer type.

Cumulative evidence suggests that the addition of platinum agents as neoadjuvant chemotherapy (NACT) could improve the pathologic complete response (pCR) rate in triple-negative breast cancer (TNBC). We aimed to develop a DNA homologous recombination (HR)-associated gene expression score to predict tumor sensitivity to platinum-based NACT in TNBC. A retrospective cohort of 127 patients who were diagnosed with TNBC and received platinum-based NACT in Fudan University Shanghai Cancer Center from 2012 to 2017 was included in this study. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), the expression levels of eight HR-associated genes were analyzed from formalin-fixed paraffin-embedded core-needle biopsy samples obtained before NACT. A random forest model was built to estimate the weight of each gene expression level and clinicopathological factors. The training set was used to modulate parameters and select the best model. The performance of the final model was evaluated in the validation set. A 4-gene (BRCA1, XRCC5, PARP1, and RAD51) scoring system was developed. TNBC patients with a higher score had a nearly fourfold likelihood of achieving pCR to platinum-based NACT compared with patients with a lower score [odds ratio (OR) = 3.878; P

Triple negative breast cancers (TNBCs) are very aggressive and have a poor prognosis due to lack of efficacious therapies. The only effective treatment is chemotherapy that however is frequently hindered by the occurrence of drug resistance. We approached this problem in vitro and in vivo on a triple negative and a hormone sensitive breast cancer cell lines: 4T1 and TS/A. A main defense mechanism of tumors is the extrusion of intracellular protons derived from the metabolic shift to glycolysis, and necessary to maintain an intracellular pH compatible with life. The resulting acidic extracellular milieu bursts the malignant behavior of tumors and impairs chemotherapy. Therefore, we investigated the efficacy of combined therapies that associate cisplatin (Cis) with proton exchanger inhibitors, such as esomeprazole (ESO) and 5‐(N‐ethyl‐N‐isopropyl)amiloride (EIPA). Our results demonstrate that in the 4T1 triple negative model the combined therapy Cis plus EIPA is significantly more effective than the other treatments. Instead, in the TS/A tumor the best therapeutic result is obtained with ESO alone. Remarkably, in both 4T1 and TS/A tumors these treatments correlate with increase of CD8+ T lymphocytes and dendritic cells, and a dramatic reduction of M2 macrophages and other suppressor myeloid cells (MDSC) in the tumor infiltrates., We show that association of cisplatin and sodium/hydrogen exchanger one inhibitors decreases tumor growth, improves the tumor microenvironment state, and increases survival more efficiently than cisplatin alone in triple negative breast cancer‐bearing mice, supporting the exploitation of this combo therapy in chemoresistant TNBCs. At variance, esomeprazole alone is more efficacious than cisplatin or various combo therapies in hormone sensitive breast cancer in mice. Thus, proton transport inhibitors should be considered as valuable nontoxic anticancer drugs.

Introduction Capecitabine is an orally administered prodrug that converts preferentially to 5-fluorouracil within tumors, resulting in enhanced concentrations of 5-fluorouracil in tumor tissue. The use of capecitabine has shown efficacy in the metastatic setting for breast cancer, and more recently, efficacy as adjuvant therapy for triple-negative breast cancer (TNBC). Capecitabine has been shown to be well tolerated with minimal side effects, but the incidence of leukoencephalopathy is rare with a risk of less than one percent. Case report We report on a 34-year-old female patient with left TNBC, moderately differentiated, stage IIB that experienced symptoms of neurotoxicity following initiation of adjuvant chemotherapy with capecitabine. Management and outcome Naranjo Algorithm Assessment score of nine indicated patient had drug-induced leukoencephalopathy leading to discontinuation of capecitabine and resolution of the neurotoxicity symptoms. Discussion Early detection of capecitabine-induced neurotoxicity by magnetic resonance imaging is crucial as symptoms may be reversible to the condition that capecitabine is immediately discontinued.