Breast Cancer 1000 Project 2010-2011 (continuation)

Breast Cancer 1000 Project 2010-2011 (continuation) Breast Cancer 1000 Project 2010-2011 Resistance to tamoxifen in breast cancer patients is a serious therapeutic problem and major efforts are underway to understand underlying mechanisms. Resistance can be either intrinsic or acquired. Our single cell sub-cloning demonstrated that many MCF7 cells are resistant de novo to tamoxifen, even without selection under pressure. Both expression profiling and an ectopic kinase expression screen led us to HSPB8, a less well-known atypical kinase that has been linked to breast cancer. Our findings indicate that HSPB8 protects breast cancers cells from tamoxifen by preventing autophagy, a process by which cells digest their own proteins. In part, tamoxifen kills breast cancer cells by triggering this process of self-digestion, an activity that HSPB8 appears to block. Interestingly, reducing HSBP8 in cells induces autophagy and causes cell death. In this proposal, we will characterize the functional role of HSPB8 through protein interactions and evaluate their role in breast cancer patients. In parallel, we will continue characterizing tamoxifen sensitive and resistant MCF7 sub-clones at genomic and proteomic level. We will expand our screening platform to find genes or pathways that are relevant to tamoxifen/fulvestrant resistance