Investigating the Role of Cdc42 in Mammary Gland Development and Breast Cancer

Breast cancer is the most frequently diagnosed cancer in women and is responsible for the largest number of cancer related deaths in women across the globe. Basic research into the roles of cancer-related genes in normal development is crucial to understanding their roles in cancer and will aid in developing new targeted therapies. Altered expression of the Rho GTPases and their regulators is associated with breast cancer. The focus of my project was to investigate the role of the Rho GTPase Cdc42 during normal mammary gland (MG) development to define the key cellular processes regulated by Cdc42, as deregulation of these processes may occur when the expression and activity of Cdc42 is elevated during the development and progression of breast cancer. Using novel conditional knockout (KO) and overexpression (OE) mouse MG models, my studies revealed for the first time critical roles for Cdc42 in mammary epithelial proliferation, migration, adhesion, stromal interactions, and morphogenesis and support a working hypothesis for how Cdc42 is functioning during MG development. In the context of normal levels of Cdc42 expression, Cdc42 participates in the Par/PKC zeta polarity complex to form tight junctions, establish epithelial polarity, and promote normal proliferation and morphogenesis of the mammary ductal tree. In the absence of Cdc42, the complete polarity complex cannot form, thus tight junctions and polarity cannot be established. Without these important initial steps the mammary epithelial cells (MECs) cannot properly organize and ultimately their ability to survive and/or contribute to MG morphogenesis is compromised, resulting in small dysmorphic mammary acini in vitro. In vivo, the KO MECs are rapidly outcompeted by wildtype (WT) MECs. Conversely, when Cdc42 is overexpressed, the polarity complex can form but the signaling downstream of this complex may become unbalanced. The tight, spatial and temporal control that is important for normal development may be tipped, causing increased contractility and aberrant migration, resulting in a dysmorphic hyperbranched MG. Evidence from our Cdc42 KO and Cdc42 OE mouse MG development models, together with published studies, suggest that Cdc42 plays an important role in breast cancer. Our work provides strong motivation for future studies investigating the role of Cdc42 in mouse mammary tumor models.