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Diseases 2018, 6(1), 5; https://doi.org/10.3390/diseases6010005

SUMOylation Regulates Transcription by the Progesterone Receptor A Isoform in a Target Gene Selective Manner

1
Department of Surgery, Anschutz Medical Campus, University of Colorado, 12801 E 17th Avenue, Aurora, CO 80045, USA
2
Department of Medicine, Anschutz Medical Campus, University of Colorado, 12801 E 17th Avenue, Aurora, CO 80045, USA
3
Department of Bioengineering, Anschutz Medical Campus, University of Colorado, 12801 E 17th Avenue, Aurora, CO 80045, USA
4
Department of Pathology, Anschutz Medical Campus, University of Colorado, 12801 E 17th Avenue, Aurora, CO 80045, USA
*
Author to whom correspondence should be addressed.
Received: 4 December 2017 / Revised: 27 December 2017 / Accepted: 29 December 2017 / Published: 2 January 2018
(This article belongs to the Section Oncology)
Full-Text   |   PDF [1820 KB, uploaded 23 January 2018]   |  

Abstract

Luminal breast cancers express estrogen (ER) and progesterone (PR) receptors, and respond to endocrine therapies. However, some ER+PR+ tumors display intrinsic or acquired resistance, possibly related to PR. Two PR isoforms, PR-A and PR-B, regulate distinct gene subsets that may differentially influence tumor fate. A high PR-A:PR-B ratio is associated with poor prognosis and tamoxifen resistance. We speculate that excessive PR-A marks tumors that will relapse early. Here we address mechanisms by which PR-A regulate transcription, focusing on SUMOylation. We use receptor mutants and synthetic promoter/reporters to show that SUMOylation deficiency or the deSUMOylase SENP1 enhance transcription by PR-A, independent of the receptors’ dimerization interface or DNA binding domain. De-SUMOylation exposes the agonist properties of the antiprogestin RU486. Thus, on synthetic promoters, SUMOylation functions as an independent brake on transcription by PR-A. What about PR-A SUMOylation of endogenous human breast cancer genes? To study these, we used gene expression profiling. Surprisingly, PR-A SUMOylation influences progestin target genes differentially, with some upregulated, others down-regulated, and others unaffected. Hormone-independent gene regulation is also PR-A SUMOylation dependent. Several SUMOylated genes were analyzed in clinical breast cancer database. In sum, we show that SUMOylation does not simply repress PR-A. Rather it regulates PR-A activity in a target selective manner including genes associated with poor prognosis, shortened survival, and metastasis. View Full-Text
Keywords: breast cancer; progesterone receptors; SUMOylation; tamoxifen resistance breast cancer; progesterone receptors; SUMOylation; tamoxifen resistance
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Abdel-Hafiz, H.A.; Dudevoir, M.L.; Perez, D.; Abdel-Hafiz, M.; Horwitz, K.B. SUMOylation Regulates Transcription by the Progesterone Receptor A Isoform in a Target Gene Selective Manner. Diseases 2018, 6, 5.

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