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This study helps to define the implications of Breast Cancer Anti-estrogen Resistant 3 (BCAR3) in breast cancer and extends current understanding of its molecular mechanism of action. BCAR3 has been shown to promote cell proliferation, migration and attachment to extracellular matrix components. However, in a cohort of metastatic breast cancer patients who received Tamoxifen treatment, high BCAR3 mRNA levels associate with favorable progression free survival outcome. These results suggest that, besides the established roles, BCAR3 may have additional mechanisms of action that regulates breast cancer aggressive phenotype. In this study, we investigate whether BCAR3 is a novel antagonist of the canonical Transforming Growth Factor beta (TGF?) pathway, which induces potent migration and invasion responses in breast cancer cells.


We surveyed functional genomics databases for correlations between BCAR3 expression and disease outcomes of breast cancer patients. We also studied how BCAR3 could regulate the TGF?/Smad signaling axis using Western blot, co-immunoprecipitation and luciferase assays. In addition, we examined whether BCAR3 could modulate TGF?-induced cell migration and invasion, using an automatic life content imaging system and a confocal microscopy imaging-based matrix degradation assay, respectively.


Relatively low levels of BCAR3 expression in primary breast tumors correlates with distant metastasis free survival (DMFS) and relapse free survival (RFS) poor outcomes. We also found a strong correlation between the loss of heterozygosity at BCAR3 gene alleles and lymph node invasion in human breast cancer, further suggesting a role for BCAR3 in preventing disease progression. In addition, we found BCAR3 to inhibit Smad activation, Smad-mediated gene transcription, Smad-dependent cell migration and matrix digestion in breast cancer cells. Furthermore, we found BCAR3 to be down-regulated by TGF? through proteasome degradation, defining a novel positive feedback loop mechanism downstream of the TGF?/Smad signaling pathway.


BCAR3 is considered to be associated with aggressive breast cancer phenotypes. However, our results indicate that BCAR3 acts as a putative suppressor of breast cancer progression by inhibiting the pro-metastatic TGF?/Smad signaling pathway in invasive breast tumors. These data provide new insights into BCAR3?s molecular mechanism of action and highlight BCAR3 as a novel TGF?/Smad antagonist in breast cancer.


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