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Having markers feasible for breast cancer subtyping, especially for triple negative breast cancer identification is crucial for improving the treatment outcome of such cancers. Here we explore the role of FOXA1 in characterizing triple negative breast cancers and the driving mechanisms. Through examination of the expression pattern at both transcriptional and translational levels, patient relapse-free survival analysis, immunohistochemistry staining and prediction power assessment using clinical samples, as well as functional studies, we systematically compared the role of FOXA1 in identifying triple negative and luminal type of breast cancers and explored the mechanisms driving such functionalities. We report that FOXA1 under-expression can lead to increased malignancy and cancer stemness, and is a subtyping marker identifying triple negative breast cancers rather than the luminal subtype by transcriptionally suppressing the expression of and . We are the first to systematically address the significance of FOXA1 in triple negative breast cancer identification as a biomarker and elucidate the mechanism at the molecular level, through a sequential bioinformatics analysis and experimental validations both and in clinics. Our discoveries compliment the current biomarker modalities once verified using larger clinical cohorts and improve the precision on characterizing breast cancer heterogeneity.

Somatic mutations or deletions of TP53 and PTEN in ductal carcinoma in situ lesions have been implicated in progression to invasive ductal carcinomas. A recent molecular and mutational analysis of breast cancers revealed that inactivation of tumor suppressors, p53 and PTEN, are strongly associated with triple negative breast cancer. In addition, these tumor suppressors have important roles in regulating self-renewal in normal and malignant stem cells. To investigate their role in breast carcinogenesis, we knocked down these genes in human mammary cells and in non-transformed MCF10A cells. p53 and PTEN knockdown synergized to activate pro-inflammatory interleukin-6 (IL6)/Stat3/nuclear factor κB signaling. This resulted in generation of highly metastatic epithelial-to-mesenchymal transition-like cancer stem cells resulting in tumors whose gene expression profile mimicked that found in basal/claudin-low molecular subtype within the triple negative breast tumors. Constitutive activation of this loop in transformed cells was dependent on proteolytic degradation of suppressor of cytokine signaling 3 (SOCS3) resulting in low levels of this protein in basal/claudin-low cell lines and primary tumors. In non-transformed cells, transient activation of the IL6 inflammatory loop induced SOCS3 expression leading to pathway inactivation. In transformed cells, enforced expression of SOCS3 or interfering with IL6 pathway via IL6R blockade inhibited tumor growth and metastasis in mouse xenograft models. Furthermore, circulating tumor cells were significantly reduced in tumor-bearing animals when treated with anti-IL6R antibodies. These studies uncover important connections between inflammation and carcinogenesis and suggest that blocking pro-inflammatory cytokines may be utilized as an attractive strategy to target triple negative breast tumors, which currently lacks molecularly targeted therapies.

Breast cancer (BC) is the most common cancer with the highest frequency of death among women. BC is highly heterogenic at the genetic, biological, and clinical level. Despite the significant improvements in diagnosis and treatments of BC, the high rate of cancer recurrence and resistance to treatment remains a major challenge in clinical practice. This issue is particularly relevant in Triple-Negative Breast Cancer (TNBC) subtype, for which chemotherapy remains the main standard therapeutic approach. Here, we observed that BC cells, belonging to different subtypes, including the TNBC, display an increased expression of Cockayne Syndrome group A (CSA) protein, which is involved in multiple functions such as DNA repair, transcription, mitochondrial homeostasis, and cell division and that recently was found to confer cell robustness when it is up-regulated. We demonstrated that CSA ablation by AntiSense Oligonucleotides (ASOs) drastically impairs tumorigenicity of BC cells by hampering their survival and proliferative capabilities without damaging normal cells. Moreover, suppression of CSA dramatically sensitizes BC cells to platinum and taxane derivatives, which are commonly used for BC first-line therapy, even at very low doses not harmful to normal cells. Finally, CSA ablation restores drug sensitivity in oxaliplatin-resistant cells. Based on these results, we conclude that CSA might be a very attractive target for the development of more effective anticancer therapies.

Background Pathogenic variants (PVs) of BRCA genes entail a lifetime risk of developing breast cancer in 50–85% of carriers. Their prevalence in different populations has been previously reported. However, there is scarce information regarding the most common PVs of these genes in Latin-Americans. This study identified BRCA1 and BRCA2 PV frequency in a high-risk female population from Northeastern Mexico and determined the association of these mutations with the patients’ clinical and pathological characteristics. Methods Women were divided into three groups: aged ≤ 40 years at diagnosis and/or risk factors for hereditary breast cancer ( n  = 101), aged > 50 years with sporadic breast cancer ( n  = 22), and healthy women ( n  = 72) . Their DNA was obtained from peripheral blood samples and the variants were examined by next-generation sequencing with Ion AmpliSeq BRCA1 and BRCA2 Panel using next-generation sequencing. Results PVs were detected in 13.8% group 1 patients ( BRCA1 , 12 patients; BRCA2 , 2 patients). Only two patients in group 2 and none in group 3 exhibited BRCA1 PVs. Variants of uncertain significance were reported in 15.8% patients ( n  = 16). In group 1, patients with the triple-negative subtype, PV frequency was 40% (12/30). Breast cancer prevalence in young women examined in this study was higher than that reported by the National Cancer Institute Surveillance, Epidemiology (15.5% vs. 5.5%, respectively). Conclusions The detected BRCA1 and BRCA2 PV frequency was similar to that reported in other populations. Our results indicate that clinical data should be evaluated before genetic testing and highly recommend genetic testing in patients with the triple-negative subtype and other clinical aspects.

Triple negative breast cancer (TNBC) is characterized by distinctive biological features that confer an aggressive clinical behavior. In TNBC patients, the absence of well-defined driver pathways such as hormonal receptor expression or hyperactivation of the human epidermal growth factor receptor 2 (HER2) significantly reduce the spectrum of therapeutic options, which are currently mainly confined to chemotherapy. Thus far, median overall survival for patients with metastatic TNBC is about 9-12 months with conventional cytotoxic agents. However, the heterogeneity recently revealed at a gene expression level inside the TNBC family may help inform therapeutic decisions concerning the use of chemotherapy and hopefully lead the way to novel targeted options that include immunotherapy. Eribulin, a halichondrin class antineoplastic drug, is currently recommended for treatment of HER2 negative metastatic or recurrent breast cancer (BC) previously exposed to anthracyclines and taxanes, also for patients with a TNBC. It is currently indicated from the second line of treatment. In this review, we aim to analyze a wide range of cumulated evidence on eribulin use in TNBC including preclinical studies, intervention and observational clinical trials. Data from the real-world setting and the emerging evidence increasingly substantiating the rationale for combinations with new generation treatment strategies, e.g., PARP-inhibitors, immune checkpoint inhibitors, will be also discussed.

Larger-size primary tumors are correlated with axillary metastases and worse outcomes. We evaluated the relationships among tumor size, location, and distance to nipple relative to axillary node metastases in triple-negative breast cancer (TNBC) patients, as well as the predictive capacity of imaging. We conducted a single-institution, retrospective chart review of stage I–III TNBC patients diagnosed from 1998 to 2019 who underwent upfront surgery. Seventy-three patients had a mean tumor size of 20 mm (range 1–53 mm). All patients were clinically node negative. Thirty-two patients were sentinel lymph node positive, of whom 25 underwent axillary lymph node dissection. Larger tumor size was associated with positive nodes (p < 0.001): the mean tumor size was 14.30 mm in node negative patients and 27.31 mm in node positive patients. Tumor to nipple distance was shorter in node positive patients (51.0 mm) vs. node negative patients (73.3 mm) (p = 0.005). The presence of LVI was associated with nodal positivity (p < 0.001). Tumor quadrant was not associated with nodal metastasis. Ultrasound yielded the largest number of suspicious findings (21/49), with sensitivity of 0.25 and specificity of 0.40. On univariate analysis, age younger than 60 at diagnosis was also associated with nodal positivity (p < 0.002). Comparative analyses with other subtypes may identify biologic determinants.

SummarySphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite, which regulates a broad range of physiological and pathophysiological processes. The signaling of S1P via its cell surface receptor S1PR1 has been identified to play an important role in carcinogenesis, cancer growth and survival, and tumor metastasis. In this study, we evaluated whether a monoclonal antibody against S1PR1 (S1PR1-antibody) could impose any effect on cell growth of human breast cancer SK-BR-3 and MDA-MB-231 cells. The S1PR1-antibody exhibited cytostatic effect against both cell lines at the concentration of 4000 ng/mL. Co-administration of 4000 ng/mL of the S1PR1-antibody not only potentiated the cytotoxicity of carboplatin towards the MDA-MB-231 cells but also increased the anti-proliferative effect of S1P towards the SK-BR-3 cells. Furthermore, we showed that co-administration of S1P did not sensitize the SK-BR-3 and MDA-MB-231 cells towards carboplatin.

Objective: Identifying factors that predispose patients to central nervous system (CNS) metastases may hasten disease detection and improve treatment outcomes. Methods: We reviewed the records of patients who were diagnosed with clinical stage I–III primary breast cancer at the National Cancer Center Hospital East from 2003 to 2005. Cox proportional hazard models were fitted to reveal risk factors for CNS metastases. Results: The median follow-up period after the operation was 53.5 months. Among the 591 identified patients with breast cancer, 76 experienced a relapse. Seventeen patients developed CNS metastases. Multivariate analysis indicated that the triple negative (TN) subtype (hazard ratio = 5.5) and a high Ki67 labeling index (LI; hazard ratio = 3.9) were associated with a higher risk for CNS metastases. At 4 years, the TN subtype was associated with significantly worse overall and disease-free survival rates and a higher cumulative incidence of CNS metastases compared with hormone receptor-positive/ human epidermal growth factor receptor-2-negative tumors. Breast cancers with a Ki67 LI ≥30% were also associated with lower overall and disease-free survival rates and a higher cumulative incidence of CNS metastases compared with cancers with a Ki67 LI <30%. Conclusion: TN or Ki67-overexpressing breast cancer produced earlier CNS metastases and lower disease-free and overall survival rates.

Background Hereditary triple-negative breast cancer patients have better recurrence-free survival than triple-negative sporadic ones. High expression of some of the miRNAs is related to worse overall and disease-free survival of triple-negative breast cancer patients. The attempt to associate expression level of some miRNA in triple-negative hereditary and sporadic breast cancers to disease specific survival was performed in this study. Material and methods Study group was made of 18 triple-negative breast cancer patients harboring the BRCA1 gene mutations and 32 triple-negative sporadic breast cancer patients. Quantitative amount of mir-10b, mir-21, mir-29a, mir-31, and mir-214 by real-time PCR was assessed. The disease-specific survival in relation of high and low levels of some of the miRNAs was analyzed using Log-rank (Mantel-Cox) test. Results MiR-214 showed significantly higher expression level in sporadic tissues than in hereditary ones (p = 0.0005). Triple-negative breast cancer patients with high level of miR-214 showed significantly worse disease-specific survival than patients with low level (p = 0.0314). Conclusions Our finding suggests that miR-214 possibly could be used as a potential prognostic biomarker for triple-negative breast cancer patients.

Aims: We investigated the relationship between serum leptin concentrations and polymorphism of the leptin receptor gene and breast cancer. Methods: Serum leptin concentrations were measured by enzyme-linked immunosorbent assay in 47 women with invasive breast cancer compared with 41 age-matched controls without cancer. Genomic DNA was extracted from peripheral blood leukocytes. Genotyping of the leptin receptor gene at codon 109 (LEPR-109) was performed by polymerase chain reaction-restriction fragment length polymorphism. Results: Patients with breast cancer had a higher mean serum leptin concentration than women in the control group, but the difference was not statistically significant. Among those with breast cancer, the serum leptin concentration was higher in women with high-grade cancers (p = 0.020). The LEPR-109RR genotype was more frequent in premenopausal patients with tumors larger than 2 cm (p = 0.039) and in premenopausal women who were overweight (p = 0.029). Among patients with the LEPR-109RR genotype, higher mean serum leptin concentrations were present in those with triple-negative cancers (p = 0.048). Conclusions: Our study suggests an association between serum leptin concentration and tumor progression. LEPR-109 polymorphism in premenopausal women appears to be associated with obesity and tumor progression.