Breast Cancer Antiestrogen Resistance 3 (BCAR3) Promotes Cell Motility by Regulating Actin Cytoskeletal and Adhesion Remodeling in Invasive Breast Cancer Cells

Abstract

Metastatic breast cancer is incurable. In order to improve patient survival, it is critical to develop a better understanding of the molecular mechanisms that regulate metastasis and the underlying process of cell motility. Here, we focus on the role of the adaptor molecule Breast Cancer Antiestrogen Resistance 3 (BCAR3) in cellular processes that contribute to cell motility, including protrusion, adhesion remodeling, and contractility. Previous work from our group showed that elevated BCAR3 protein levels enhance cell migration, while depletion of BCAR3 reduces the migratory and invasive capacities of breast cancer cells. In the current study, we show that BCAR3 is necessary for membrane protrusiveness, Rac1 activity, and adhesion disassembly in invasive breast cancer cells. We further demonstrate that, in the absence of BCAR3, RhoA-dependent signaling pathways appear to predominate, as evidenced by an increase in RhoA activity, ROCK-mediated phosphorylation of myosin light chain II, and large ROCK/mDia1-dependent focal adhesions. Taken together, these data establish that BCAR3 functions as a positive regulator of cytoskeletal remodeling and adhesion turnover in invasive breast cancer cells through its ability to influence the balance between Rac1 and RhoA signaling. Considering that BCAR3 protein levels are elevated in advanced breast cancer cell lines and enhance breast cancer cell motility, we propose that BCAR3 functions in the transition to advanced disease by triggering intracellular signaling events that are essential to the metastatic process.

Genome-wide DNA methylation profiling reveals parity-associated hypermethylation of FOXA1

“…The role of FOXB2 , another FOX family gene, in cancer is not known. BCAR3 encodes a signaling molecule that plays an important role in breast cancer invasion and resistance to anti-estrogen therapies [25, 26]. Therefore, it is conceivable that epigenetic changes at these loci could affect hormonal responsiveness of breast epithelial cells and their propensity for tumorigenesis.…”

Functional roles of BCAR3 in the signaling pathways of insulin leading to DNA synthesis, membrane ruffling and GLUT4 translocation

“…Currently, the molecular identity of p95 and p60 is yet to be uncovered. The association of BCAR3 with Cas has been reported and this association is important in cell motility and metastasis [22,23]. BCAR3 and Cas co-localize at the cell membrane, and synergistically increase cell proliferation and transformation with Src oncogenes in breast cancer cells [11].…”

“…BCAR3 and Cas co-localize at the cell membrane, and synergistically increase cell proliferation and transformation with Src oncogenes in breast cancer cells [11]. Although many studies show that BCAR3 regulates cell motility [22,23], the functional role of BCAR3 in the signaling pathways of growth factors such as insulin and IGF-1 has not completely been elucidated.…”

Expression pattern of bcar3, a downstream target of Gata2, and its binding partner, bcar1, during Xenopus development

“…Bcar3 is an adaptor protein that interacts with Bcar1 (also known as p130 Crk-associated substrate (p130Cas)) to transduce signals downstream of activated integrins (Barrett et al, 2013; Cabodi et al, 2010). Bcar3 downregulates cadherin dependent cell-cell adhesion and promotes cell motility by controlling cytoskeletal remodeling in breast cancer cells (Makkinje et al, 2009; Near et al, 2009; Schrecengost et al, 2007; Sun et al, 2012; Wilson et al, 2013). Changes in cell-cell adhesion and cytoskeletal remodeling are integral components of cell movements that drive gastrulation, which brings the ectoderm and mesoderm into contact.…”