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

Diseases
Hany A Abdel-HafizKathryn B Horwitz

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-indepen...Continue Reading

References

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Citations

Oct 12, 2018·Endocrinology·Thu H Truong, Carol A Lange
Sep 13, 2019·Endocrine Reviews·Britton TrabertFrank Z Stanczyk
Jun 2, 2021·Essays in Biochemistry·Sebastian GiulianelliClaudia Lanari

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Datasets Mentioned

BETA
GSE108607

Methods Mentioned

BETA
ubiquitination
transfections
transfection
acetylation

Software Mentioned

Ingenuity Pathway Analysis
Partek Genomics Suite
Ingenuity Pathway Analysis ( IPA )
Partek Suite

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