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Growth regulation and steroid hormone resistance in breast cancer

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Our research focuses on breast cancer, and how the steroid hormone agonists - estradiol and progesterone - enhance growth of these tumors. Therefore, their treatment often involves the use of steroid antagonists, which interfere with deleterious effects of the agonists. Although tumors often respond well to antagonists initially, and undergo remission, eventually tumors acquire resistance to antagonists and resume growing. I will discuss studies dealing with growth regulatory mechanisms of progesterone, focusing on the role of cyclins; cyclin-dependent kinases and cdk inhibitors; and cross-talk between progesterone and epidermal growth factor (EGF) signaling. The latter involves analysis of mechanisms by which progesterone and EGF cooperate to activate mitogen-activated protein kinase (MAPK) and STAT signaling pathways, and regulate transcription of the cdk inhibitor, p21. Additionally we show that MAPK phosphorylation of progesterone receptors, at serine 294, leads to ligand-dependent receptor downregulation by the ubiquitin-26S proteasome pathway. I will also describe the isolation and characterization of transcriptional coactivators and corepressors that either enhance or inhibit transcription by antagonist-occupied steroid receptors. We test the idea that the ratio of these coregulators determines whether tamoxifen is inhibitory or not, using breast cancers taken from tamoxifen-responsive and -resistant patients.

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Horwitz, K. Growth regulation and steroid hormone resistance in breast cancer. Breast Cancer Res 2, S.09 (2000) doi:10.1186/bcr132

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Keywords

  • Breast Cancer
  • Tamoxifen
  • Epidermal Growth Factor
  • Progesterone
  • Estradiol