Exploring functional links between matrix stiffness, micro RNAs and HoxA9 dependent regulation of BRCA1 and mammary cell survival and tumorigenesis.

Stromal-epithelial interactions drive development and maintain tissue homeostasis through a network of soluble and insoluble factors that operate within a three-dimensional (3D) tissue. Genetic and epigenetic changes in mammary epithelial cells (MECs) cooperate with a modified tissue microenvironment to drive malignant transformation of the breast. We have been studying how altered expression of developmental regulators contributes to breast tumorigenesis and have specifically focused on investigating their influence on integrin expression and/or adhesion activity. Homeobox genes play a critical role in tissue development, are frequently lost in tumors, and can regulate integrin and extracellular matrix (ECM) expression. Global expression analysis of matched tumor/normal breast tissue revealed that HoxA9 expression was significantly lower in the tumors. HoxA9 represses the malignant phenotype of breast cancer cells in vivo as well as in 3D rBM and this reversion is coincident with BRCA1 induction and normalization of adhesion and integrin expression. Accordingly, we are exploring functional and mechanistic links between HoxA9, BRCA1 and integrin-dependent tissue behavior. In addition, we are studying how changes in the biomechanical properties of the ECM during normal development and mammary tumorigenesis can influence HoxA9 expression.