Cellular Signaling Networks in Breast Cancer

Breast cancer is the second most commonly diagnosed cancer worldwide and one of the most heterogeneous cancers at cellular and molecular level. Incidence of breast cancer is much higher in the developed world suggesting that aspects of a modern western lifestyle may influence the onset and progression of this disease. Unhealthy habits (excessive caloric diets, irregular daily rhythms of living) and hormonal/behavioral stresses lead to profound alterations of cellular homeostasis that can affect the efficacy of several processes ensuring genome integrity such as the DNA damage response, which comprises DNA repair, DNA damage checkpoints and transcriptional reprogramming. Besides oncogenic drivers underpinning breast ductal carcinomas, alteration of relevant signaling nodes can critically impinge on DNA integrity-related cellular networks to strength genome instability and cancer progression. Our studies indicate that the serine/threonine kinase GRK2 is emerging as a regulatory node of oncogenic signaling modules by its ability to rewire the ubiquitination and acetylation of manifold proteins in transformed cells. GRK2 stimulates the activity of the E3 ligase Mdm2, which is a key player in cellular transformation by means of the inhibition of tumor suppressors (p53) and modulation of molecules involved in cell-cycle control, DNA damage response and cellular stress handling. The goal of the project is to define the regulatory intertwinement of GRK2 with Mdm2 in transformed mammary epithelial cells and functional consequences of the GRK2-mediated phosphorylation of Mdm2 in sensing DNA damage and arresting cell cycle progression