UCSF

Mammary epithelial cell (MEC)-extracellular matrix (ECM) interactions are critical for normal breast tissue development, differentiation and homeostasis by engaging a repertoire of ECM adhesion receptors including integrins to activate signaling processes that control MEC differentiation, proliferation and survival. Malignant progression alters MEC responsiveness to ECM cues and is highlighted by the observation that the expression of integrins is altered during breast tumor progression. The molecular basis for altered integrins in breast tumors and the regulation of integrin changes during malignant transformation are less understood. The goal of my thesis is to test the hypothesis that oncogene-dependent transformation promotes breast tumor progression through regulating changes in ECM responsiveness via α5 integrin through targeting of the SWI/SNF chromatin remodeling protein BRM. I found that oncogene-driven transformation depends upon increased expression of α5 integrin to promote MEC growth and survival in three-dimensional (3D) cultures and implicates the SWI/SNF chromatin remodeling protein, Brahma (BRM) in the regulation of tumor-driven ECM responsiveness changes. I also observed decreased BRM expression in breast cancer cell lines and abrogation of BRM in non-malignant MECs enhanced cell motility and anchorage independent growth and upregulated a gene program associated with breast tumor progression. Microarray analysis of breast cancer patient samples revealed that reduced BRM expression correlated with increased disease recurrence and morbidity. Whether BRM is a bona fide tumor suppressor in breast cancers and whether targeting the re-expression of BRM in breast tumors is a viable therapeutic target remains an area of active research. Nevertheless, regaining ECM responsiveness in breast tumor cells by manipulating chromatin is without precedent and forms the foundation for future investigations into the epigenetic mechanisms governing ECM responsiveness and may lead to the discovery of novel molecular targets in the treatment of breast cancer.