Regulation of TGF-Beta Signal Transduction Pathways in Breast Cancer Cells

摘要

My research goal under BCRP fellowship was to address the fundamental mechanism of TGF-beta signaling both in normal cell and cancer cells and its possible relevance to breast cancer development. Seven papers have been published or submitted during the grant period including three first-author publications. I have been involved in characterizing key signaling components (Smad3 and TFE3) and studied their function in normal TGF-beta signaling in epithelial cells. Using various experimental approaches, I discovered two distinct mechanisms by which TGF-beta signaling is altered in cancer cells. Firs, I discovered a novel mechanism by which ski oncoprotein abrogates TGF-beta signaling. Second, I found activation of Ras oncogene could disrupt TGF-beta signaling by sequestration of tumor suppressor p27 in the cytoplasm preventing its association with cdk2/cyclin E complexes. Finally, I have developed very powerful expression cloning strategies for isolating novel intracellular signal transduction proteins that mediate the pathway(s) by which TGF-beta regulates cell growth and gene expression.