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• W2063531057 abstract "Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DCAromatase inhibitors (AI), which block the synthesis of estrogen and render an “estrogen-deprived” environment, are used extensively to treat postmenopausal ER positive breast cancers (BC). Unfortunately, 15-60% of breast cancer patients will relapse within 3-5 years of AI treatment. Therefore, it is crucial to understand the mechanisms involved in AI-resistance to identify new therapeutic targets. Our laboratory has previously reported the development of an estrogen-deprivation (ED) resistant cell line known as MCF7:5C cells which mimic the AI-resistant BC and can grow spontaneously in vitro as well as form xenograft tumors in the athymic mice in absence of estrogen (ref: Lewis et al., JNCI, 2005; 97(23):1746-59).Recent clinical studies have indicated over-expression of a transcription factor, cMYC oncogene and the genes regulated by cMYC as one of the major predictor in the aromatase inhibitor resistant BC. However, the mechanism by which the cMYC oncogene is over-expressed remains largely elusive. Using MCF7:5C cells as a model for ER positive, AI-resistant BC cells; we investigated the levels of cMYC oncogene and compared it with the parental MCF7 cells which do not proliferate in the absence of estrogen. We found that cMYC protein as well as mRNA levels were approximately 3 fold higher in MCF7:5C cells as compared to MCF7 cells. Treating the cells with a cMYC inhibitor, 10058-F4, or with cMYC si RNA decreased the proliferation and the number of ‘S’ phase cells in MCF7:5C cells. To elucidate the underlying mechanism responsible for the elevated transcription of cMYC we examined the promoter of the cMYC gene and found that the recruitment of phospho-serine-2-RNA pol II (a marker of RNA elongation) was significantly higher in MCF7:5C cells as compared to the parental MCF7 cells. Further investigation revealed that activated CDK9 levels were responsible for phosphorylating serine 2 RNA pol II in MCF7:5C cells. Inhibition of CDK9 decreased the levels of total phospho-serine-2 RNA pol II and the cMYC mRNA and also inhibited the estrogen-independent proliferation of MCF7:5C cells. This study strongly suggests CDK9 as a potential therapeutic target which mediates elevated transcription of cMYC, which in turn is responsible for estrogen-independent growth of AI-resistant BC cells.Grant Support: This work (VCJ) was supported by the Department of Defense Breast Program under Award no: W81XWH-06-1-0590 Center of Excellence; the Susan G Komen For The Cure Foundation under Award no: SAC100009; National Cancer Institute, Award no: P30CA051008.Citation Format: Surojeet Sengupta, Michael C. Biarnes, V. Craig Jordan. Transcriptional deregulation of cMYC as a critical determinant of estrogen independence and aromatase inhibitor resistance in breast cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5642. doi:10.1158/1538-7445.AM2013-5642" @default.
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• W2063531057 date "2013-04-15" @default.
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• W2063531057 title "Abstract 5642: Transcriptional deregulation of cMYC as a critical determinant of estrogen independence and aromatase inhibitor resistance in breast cancers." @default.
• W2063531057 doi "https://doi.org/10.1158/1538-7445.am2013-5642" @default.
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