Session: MON 355-388-Sex Hormone Receptor Action & Reaction
Poster Board MON-374
Mugdha Patki*1, 2, Marcela d’Alincourt Salazar1, Robert Trumbly1 and Manohar Ratnam2
1Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, Ohio; 2Karmanos Cancer Institute and Department of Oncology at Wayne State University, Detroit, Michigan
Most breast tumors are estrogen receptor (ER)-positive and require estrogen for their growth and survival. Long-term adjuvant therapies that disrupt estrogen signaling, in particular tamoxifen and aromatase inhibitors, are a mainstay in breast cancer treatment; however, resistant tumors emerge in about half the cases after 3-5 years of treatment. The principal focus of mechanistic studies of tamoxifen has been on estrogen activated genes. Gene repression by estrogen and its antagonism by adjuvants have unclear physiological and therapeutic consequence in breast cancer. Our laboratory has previously identified a non-classical mechanism of gene repression by estrogen which is sensitive to tamoxifen. In this study, we found that estrogen-repressed genes but not estrogen-activated genes overlapped the gene overexpression signature of clinical progression of ductal carcinoma in situ to invasive ductal carcinoma. An extensive gene ontology analysis revealed that genes repressed by estrogen are enriched for functions known to collectively support breast cancer progression. In ER-positive breast cancer cells estrogen inhibited invasiveness in a manner that was opposed by tamoxifen. The gene repression by estrogen was generally independent of ErbB2 regulation or tamoxifen resistance. It involved ER binding at non-classical chromatin sites that was prevented by tamoxifen and trended toward greater estrogen sensitivity than classical gene activation. NCoRI and Pax2 were the major corepressors that supported estrogen repression of the tumor progression genes. The findings impact conceptualizing outcome in estrogen replacement therapy and in breast cancer chemoprevention. They also provide a possible mechanistic basis to develop estrogen antagonist drugs that are superior to tamoxifen.
Nothing to Disclose: MP, MDS, RT, MR
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