Abstract 59: Effects of Cdc42 overexpression on the developing mammary gland

Abstract

Abstract The Rho GTPase Cdc42 is overexpressed and hyperactivated in human breast cancer; however, its precise role during normal mammary gland (MG) development and the stochastic process of mammary tumor formation in vivo remains unknown. We, therefore, investigated the effects of Cdc42 knockout and overexpression during mammary morphogenesis using conditional mouse models. Previously, we demonstrated that loss of Cdc42 prevents primary mammary acinus formation in a three-dimensional (3D) in vitro culture system. Defects in proliferation, survival, and polarity contributed to the aberrant phenotype. Furthermore, preliminary studies using MMTV-cre mice to conditionally delete Cdc42 in ∼30% of mammary epithelial cells (MECs) in the developing MG suggest that Cdc42 knockout MECs are outcompeted by wildtype MECs in vivo. To investigate the effects of Cdc42 overexpression on MG development, and ultimately tumorigenesis, we generated tetracycline-regulatable Cdc42 overexpressing mice. Interestingly, Cdc42 overexpression results in aberrant terminal end bud (TEB) morphogenesis, increased ductal branching, and ductal dilation, suggesting that Cdc42 overexpression increases MEC proliferation and invasion and may cause defects in cell adhesion and tight junctions. Consistent with these data, Cdc42 overexpressing MECs give rise to dysmorphic, invasive acini in 3D culture assays. Taken together, these data demonstrate that Cdc42 is a key regulator of proliferation and tissue architecture in the developing MG and suggest that Cdc42 overexpression may contribute to tumor formation by disrupting these processes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 59. doi:1538-7445.AM2012-59