Rosalie Sears International Association for Breast Cancer Research 2014

Rosalie Sears

My lab studies cellular signaling pathways that control tumor cell state with a focus on their regulation of the c-Myc oncoprotein. c-Myc is constitutively overexpressed in the majority of human tumors and studies have demonstrated that this affects both tumor cell state (proliferation, differentiation, metabolism) as well as cross-talk with the tumor microenvironment and vasculature. We have identified a complex signaling pathway that coordinately regulates c-Myc turnover. This pathway targets two conserved phosphorylation sites in c-Myc, Threonine 58 (T58) and Serine 62 (S62), which have opposing effects on c-Myc stability and activity. c-Myc is aberrantly stabilized in many tested human cancer cell lines and primary patient tumor samples, including breast and pancreas, in association with elevated S62 phosphorylation and reduced T58 phosphorylation. This provides a pathway for therapeutic intervention targeting post-translational regulation of c-Myc in human cancer. We are testing potential therapeutics targeting this pathway for the treatment of breast and pancreatic cancer in vivo using orthotopic cancer cell line xenografts, patient derived xenografts, and novel spontaneous mammary gland and pancreas cancer mouse models we have developed.