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

Daniel Perez,Kathryn Horwitz,Mohamed Abdel-Hafiz,Michelle Dudevoir,Hany Abdel-Hafiz

doi:10.3390/diseases6010005

Daniel Perez, Kathryn Horwitz + Show 3 more

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https://doi.org/10.3390/diseases6010005

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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.

Highlights

Actions of progesterone (P) are mediated by two progesterone receptor (PR) isoforms calledPR-A and PR-B
They are co-expressed in the normal breast, but equimolarity may be disrupted in breast cancers [1]
Use of promoters, synthetic promoters, demonstrates that SUMOylation suppressessuppresses transcription by PR-B and is relieved this study demonstrates that SUMOylation transcription byPR-A, PR-B which and PR-A, which by is deSUMOylation

Summary

Introduction

Actions of progesterone (P) are mediated by two progesterone receptor (PR) isoforms called. They are co-expressed in the normal breast, but equimolarity may be disrupted in breast cancers [1]. The two isoforms have different physiological functions and regulate different sets of genes [1]. Tissue-specific differences in their distribution patterns may account for dissimilar organ-specific P effects [2]. In the mouse mammary gland, PR-B is important for ductal side-branching and the labulo-alveolar development of pregnancy, while PR-A deficiency results in uterine and ovarian abnormalities and infertility.

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