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Background: Mechanically gated PIEZO channels lead to an influx of cations, activation of additional Ca2+ channels, and cell depolarization. This study aimed to investigate PIEZO2's role in breast cancer. Methods: The clinical relevance of PIEZO2 expression in breast cancer patient was analyzed in a publicly available dataset. Utilizing PIEZO2 overexpressed breast cancer cells, and in vitro and in vivo experiments were conducted. Results: High expression of PIEZO2 was correlated with a worse survival in triple-negative breast cancer (TNBC) but not in other subtypes. Increased PEIZO2 channel function was confirmed in PIEZO2 overexpressed cells after mechanical stimulation. PIEZO2 overexpressed cells showed increased motility and invasive phenotypes as well as higher expression of SNAIL and Vimentin and lower expression of E-cadherin in TNBC cells. Correspondingly, high expression of PIEZO2 was correlated with the increased expression of epithelial–mesenchymal transition (EMT)-related genes in a TNBC patient. Activated Akt signaling was observed in PIEZO2 overexpressed TNBC cells. PIEZO2 overexpressed MDA-MB-231 cells formed a significantly higher number of lung metastases after orthotopic implantation. Conclusion: PIEZO2 activation led to enhanced SNAIL stabilization through Akt activation. It enhanced Vimentin and repressed E-cadherin transcription, resulting in increased metastatic potential and poor clinical outcomes in TNBC patients. [ABSTRACT FROM AUTHOR]

Background: Cytotoxic T-lymphocyte (CTL) infiltration into tumor is a positive prognostic factor in breast cancer. High tumor mutational burden (TMB) is also considered as a predictor of tumor immunogenicity and response to immunotherapy. However, it is unclear whether the infiltration of functional CTL simply reflects the TMB or represents an independent prognostic value. Methods: Utilizing The Cancer Genome Atlas (TCGA) breast cancer cohort, we established the Functional Hotness Score (FHS). The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed in a total of 3011 breast cancer patients using TCGA, METABRIC and metastatic breast cancer (MBC) cohort GSE110590. Results: We established FHS, based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors, which delivered the best prognostic value among some gene combinations. Breast cancer patients with the high-FHS tumors showed significantly better survival. FHS was lower in the MBCs. Triple-negative breast cancer (TNBC) showed the highest FHS among subtypes. FHS predicted patient survival in hormone receptor (HR)-negative, especially in TNBC, but not in HR-positive breast cancer. FHS predicted patient prognosis independently in TNBC. The high-FHS TNBCs showed not only higher CD8+ T cell infiltration, but also enhanced broader type-1 anti-cancer immunity. The patients with the high-FHS tumors showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified a unique subset of patients who do not recur over time in TNBC. Conclusion: TNBCs with high FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with enhanced anti-cancer immunity regardless of TMB. FHS constitutes an independent prognostic marker of survival, particularly robustly when combined with TMB in TNBC. [ABSTRACT FROM AUTHOR]

Metastatic breast cancer, despite many medical advances, remains an incurable disease. Therefore, treatments that overcome cancer cell resistance to current treatments are needed to decrease relapse and onset of metastatic disease. Aurora-A kinase has been implicated in breast cancer tumorigenesis and progression of the disease. It has also been shown to play a role in increasing a more chemotherapy-resistant, mesenchymal phenotype, and cells with stem cell-like characteristics. Pre-clinical data have been encouraging with inhibitors of Aurora-A kinase signaling, showing decreased proliferation and increased sensitivity of breast cancer cells to both hormonal and chemotherapy treatments. In early clinical trials with Alisertib, the most clinically advanced Aurora-A inhibitor, there have been early signals of activity, especially in the HR+ and HER2-positive breast cancer patient population. There is ongoing research in developing further specific Aurora-A and pan-Aurora kinase inhibitors and to identify biomarkers to show appropriate patient population for treatment. The first breast cancer-specific clinical trial with an Alisertib and Fulvestrant combination has completed accrual, and we are eagerly awaiting data to confirm that Aurora-A kinase inhibition has a role in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point towards the ‘cross-talk’ between ERα and MAPK signaling pathways as a key oncogenic axis responsible for the development of estrogen-independent growth of breast cancer cells that are initially ERα+ and hormone sensitive. In this study we employed a metastatic breast cancer xenograft model harboring constitutive activation of Raf-1 oncogenic signaling to investigate the mechanistic linkage between aberrant MAPK activity and development of endocrine resistance through abrogation of the ERα signaling axis. We demonstrate for the first time the causal role of the Aurora-A mitotic kinase in the development of endocrine resistance through activation of SMAD5 nuclear signaling and down-regulation of ERα expression in initially ERα+ breast cancer cells. This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis. We postulate such therapy to result in the selective eradication of endocrine resistant ERαlow/− cancer cells from the bulk tumor with consequent benefits for breast cancer patients. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) patients experience increased stress with elevated cortisol levels, increasing risk of cancer recurrence. Cortisol binds to a cytoplasmic receptor, glucocorticoid receptor (GR) encoded by GR gene (NR3C1). We hypothesized that not only cancer cells, but even immune cells in the tumor microenvironment (TME) may contribute to GR expression in bulk tumor and influence prognosis. To test this, mRNA expression data was accessed from METABRIC and TCGA. "High" and "low" expression was based on highest and lowest quartiles of NR3C1 gene expression, respectively. Single-cell sequencing data were obtained from GSE75688 and GSE114725 cohorts. Computer algorithms CIBERSORT, Gene Set Enrichment Analysis and TIMER were used. GR-high BC has better median disease-free and disease-specific survival. Single cell sequencing data showed higher GR expression on immune cells compared to cancer and stromal cells. Positive correlation between GR-high BC and CD8+ T-cells was noted. In GR-high tumors, higher cytolytic activity (CYT) with decreased T-regulatory and T-follicular helper cells was observed. High GR expression was associated with lower proliferation index Ki67, enriched in IL-2_STAT5, apoptosis, KRAS, TGF-β signaling, and epithelial-to-mesenchymal transition. Immune cells significantly contribute to GR expression of bulk BC. GR-high BC has a favorable TME with higher CYT with favorable outcomes. [ABSTRACT FROM AUTHOR]

Sorafenib is an oral, small-molecule receptor, tyrosine kinase inhibitor with antiproliferative as well as antiangiogenic properties. The multiple cellular targets of sorafenib include serine/threonine kinase Raf, vascular endothelial growth factor receptors 1, 2, 3, platelet-derived growth factor-b, Flt-3, and c-Kit. Sorafenib has demonstrated preclinical activity against several tumor types and has been approved for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, and iodine-refractory thyroid carcinoma. In this review we summarize the clinical antitumor activity of sorafenib in solid tumors, with focus on breast, ovarian, and glioblastoma cancers. We review available data from multiple phase Ib and phase II trials with sorafenib alone or in combination with other agents, and highlight the most encouraging clinical data which will guide the future directions of research. We also discuss biomarker research and the need for better predictive markers for response to sorafenib. Although sorafenib is relatively well tolerated, there are multiple toxicities that can result in dose reductions and discontinuations that are especially evident in combination therapy trials. In the next several years new data from large phase III trials will become available, which might broaden the clinical indication of sorafenib to adjuvant settings and/or other malignancies. Better understanding of its mechanism of action and clinical activity will assist in clinical management of patients. [ABSTRACT FROM AUTHOR]