Triple-Negative Breast Cancers (TNBCs) constitute roughly 10-20% of breast
cancers and are associated with poor clinical outcomes. Previous work from our laboratory and others has determined that the cytoplasmic adaptor
protein Breast Cancer Antiestrogen Resistance 3 (BCAR3) is an important promoter of cell motility and invasion of
breast cancer cells. In this study, we use both in vivo and in vitro approaches to extend our understanding of BCAR3 function in TNBC. We show that BCAR3 is upregulated in
ductal carcinoma in situ (
DCIS) and invasive
carcinomas compared to normal mammary tissue, and that survival of TNBC patients whose
tumors contained elevated BCAR3
mRNA is reduced relative to individuals whose
tumors had less BCAR3
mRNA. Using mouse orthotopic
tumor models, we further show that BCAR3 is required for efficient TNBC
tumor growth. Analysis of publicly available
RNA expression databases revealed that MET receptor signaling is strongly correlated with BCAR3
mRNA expression. A functional role for BCAR3-MET coupling is supported by data showing that both
proteins participate in a single pathway to control proliferation and migration of TNBC cells. Interestingly, the mechanism through which this functional interaction operates appears to differ in different genetic backgrounds of TNBC, stemming in one case from potential differences in the strength of downstream signaling by the MET receptor and in another from BCAR3-dependent activation of an autocrine loop involving the production of HGF
mRNA. Together, these data open the possibility for new approaches to personalized
therapy for individuals with TNBCs.