Breast Cancer 1000 Project Breast Cancer 1000 Project 2009-2010 The LaBaer group is pursuing studies to identify and characterize genes that regulate critical events involved in the progression of breast cancer and understanding the development of resistance to anti-estrogen drug treatment. We derived matched drug sensitive and resistant breast cancer cells that allow us to ask what changes occur in a breast cancer cell when it becomes drug resistant. We found a signature of 67 genes that are differently expressed in resistant vs. sensitive cells. In two different clinical studies, women whose tumors matched the resistance pattern had a significantly greater likelihood of early relapse while on tamoxifen. Such signatures may prove useful in informing women about whether they need more aggressive surveillance while on tamoxifen or if alternatives should be considered. We also used the collection of breast cancer related genes (BC1000) that we produced with BCRF support to identify 31 proteins that make sensitive cells become resistant. One of these, called HSPB8, is a kinase that repeatedly made these cells resistant. Overexpression of this gene in womens tumors predicted poor clinical outcome in patients. When produced in tamoxifen sensitive cells, HSPB8 makes them resistant to the drug; whereas, reducing HSPB8 in resistant cells causes them to die by inducing autophagy, a process by which cells digest their own proteins in times of nutrient stress. Taken too far, autophagy can lead to cell death. Further studies in this period have shown that autophagy plays an important role in the cell death of cultured breast cancer cells when treated with tamoxifen and that rescue from autophagy may provide an escape mechanism from the drug. We hope that defining gene pathways that are responsible for drug resistance will lead to combined treatments that will more effectively treat resistant cancers. In addition, the LaBaer group has continued to develop, maintain and distribute a large gene collection, the BC1000, for studies by the breast cancer community. 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
|Effective start/end date||10/1/09 → 9/30/10|
- Breast Cancer Research Foundation: $334,604.00
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