Publications

Abstract

Although the multi-functional, pro-survival protein, BAG-1 is frequently overexpressed in breast cancers, its role in the development or maintenance of the malignant state remains unclear. Here, we have utilized the established MCF-10A 3-dimensional (3-D) model of mammary morphogenesis as a biologically relevant system with which to determine how BAG-1 expression may influence the development of breast cancer. When cultured in 3-D, MCF-10A cells undergo a highly-regulated morphogenic program leading to the development of polarized acinar structures containing a central, hollow lumen formed in part, through the induction of BIM-dependent apoptosis. BAG-1 overexpression resulted in an attenuation of this normal apoptotic program characterized by a significantly increased number of acini with filled lumens ? a phenotype commonly observed in ductal carcinoma in situ. BAG-1?s effects were associated with an activation of RAF-1 ? a known binding partner of BAG-1, enhanced signaling through the MAP kinase pathway and a decrease in BIM expression. Reversal of the BAG-1-associated survival phenotype by the MEK inhibitor, U0126 implicates the RAF-1/ERK signaling pathway as a major mediator of BAG-1?s effects in this model. As BAG-1 expression is often elevated in preinvasive breast cancers, these findings support a possible role for BAG-1 as an early contributor to the malignant process in the breast.