ERRα

Breast cancer progression, metastasis and recurrence are largely driven by breast cancer stem cells (BCSCs), which constitute a subset of tumor cells exhibiting stem cell characteristics. In this study, we evaluated the role of estrogen-related receptor alpha (ERRα) in the migration, invasion and angiogenesis of BCSCs. The inhibition of ERRα using XCT790 or knockdown of ERRα using shRNA inhibited the mammosphere formation efficiency, as well as the migration and invasion of BCSCs derived from the mammospheres of MCF7 and MDA-MB-231 (MB231) cells. Conversely, the overexpression of ERRα significantly increased the migration and invasion of BCSCs derived from the mammosphere. In addition, the XCT790 treatment or shERRα significantly downregulated the epithelial-mesenchymal transition (EMT), as evidenced by the downregulation in the expression of vimentin, Snail, Slug and N-cadherin in the mammospheres of MCF7 and MB231 cells. The chorioallantoic membrane assay showed that the conditioned media from XCT790-treated and shERRα cells significantly inhibited blood vessel formation and vessel length. Furthermore, XCT790 treatment or shERRα also downregulated the expression of molecular markers of angiogenesis, such as VEGF-A and Ang-2 in the mammospheres. Conversely, the overexpression of ERRα in MCF7 cells significantly increased both EMT and angiogenesis. These findings suggest that ERRα inhibits the migration, invasion and angiogenesis of BCSCs, suggesting as a potential target for breast cancer therapy.

Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression and activity in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance, basal-like differentiation, and invasion. A functional drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-α signaling. Among these, the Transforming Growth Factor-β and the Janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced modulation of ER-α activity. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-α expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.

Beauvericin (BEA) is a cyclic depsipeptide secondary metabolite of Fusarium species. It causes chemical hazards in food products and exists in an environment containing soil and various food types. On the other hand, the purified BEA has various biological activities and is regarded as a potential candidate for pharmaceutical research. This study was performed to assess the anti-proliferation activity of BEA against human breast cancer cells by regulating the estrogen receptor-alpha (ERα)/p38 pathway. TA and BA assays verified that BEA is a completed ER antagonist. Additionally, BEA suppressed cell proliferation in the anti-proliferation assay involving ER-positive human breast cancer cells co-treated with BPA and BEA. In respect to an anti-proliferation activity, the BPA-induced phosphorylation of p38 protein was inhibited in the presence of BEA. These results suggested that BEA exerts inhibitory potentials on endocrine disrupting effect and possibly acts as a natural therapeutic material for human estrogen hormonal health.