The object of this proposal is to study the regulation and the bioactivity of the A-protein (Mr 94,000) and B-protein (Mr 120,000) of human breast cancer progesterone receptors (PR). We will use progestin responsive breast cancer cell lines, in situ photoaffinity labeling, anti-receptor antibodies, and PR cDNA probes to: a) study the transcriptional and/or post- transcriptional regulation of PR messages by progestins and estradiol, and assess hormonal effects on mRNA and protein turnover rates; b) determine PR gene copy number in normal and breast cancer cells where PR are over-expressed; c) analyze the processing state and the 5'- and 3'-termini of six different PR message bands; d) show, by hybrid selection and hybrid arrest translation, whether only B-receptors or both A- and B-receptors can be synthesized in vitro; d) transfect full length wild-type PR cDNA, and cDNAs in which A- or B-receptor translation start sites have been destroyed by mutation, or together, are needed for response to progestins; f) develop methods to study expression, by isolating PR-regulated messages, and by searching for progestin-regulated growth inhibitory factors in cell-conditioned media; g) address the clinical applications of some of these studies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Reproductive Endocrinology Study Section (REN)
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University of Colorado Denver
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Abdel-Hafiz, Hany A; Dudevoir, Michelle L; Perez, Daniel et al. (2018) SUMOylation Regulates Transcription by the Progesterone Receptor A Isoform in a Target Gene Selective Manner. Diseases 6:
Abdel-Hafiz, Hany A; Horwitz, Kathryn B (2015) Role of epigenetic modifications in luminal breast cancer. Epigenomics 7:847-62
Ogba, Ndiya; Manning, Nicole G; Bliesner, Brian S et al. (2014) Luminal breast cancer metastases and tumor arousal from dormancy are promoted by direct actions of estradiol and progesterone on the malignant cells. Breast Cancer Res 16:489
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Knox, Aaron J; Scaling, Allison L; Pinto, Mauricio P et al. (2014) Modeling luminal breast cancer heterogeneity: combination therapy to suppress a hormone receptor-negative, cytokeratin 5-positive subpopulation in luminal disease. Breast Cancer Res 16:418
Abdel-Hafiz, Hany A; Horwitz, Kathryn B (2014) Post-translational modifications of the progesterone receptors. J Steroid Biochem Mol Biol 140:80-9
Jambal, Purevsuren; Badtke, Melanie M; Harrell, J Chuck et al. (2013) Estrogen switches pure mucinous breast cancer to invasive lobular carcinoma with mucinous features. Breast Cancer Res Treat 137:431-48
Harvell, Djuana M E; Kim, Jihye; O'Brien, Jenean et al. (2013) Genomic signatures of pregnancy-associated breast cancer epithelia and stroma and their regulation by estrogens and progesterone. Horm Cancer 4:140-53
Haughian, James M; Pinto, Mauricio P; Harrell, J Chuck et al. (2012) Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch. Proc Natl Acad Sci U S A 109:2742-7
Abdel-Hafiz, Hany A; Horwitz, Kathryn B (2012) Control of progesterone receptor transcriptional synergy by SUMOylation and deSUMOylation. BMC Mol Biol 13:10

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