Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells

Andrea R. Daniel, Carol A. Lange

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

In advanced breast tumors, protein kinases are upregulated and steroid hormone receptors often function independently of ligand. Herein, we explored mechanisms of ligand-independent progesterone receptor (PR) activity. We showed previously that growth factorinduced phosphorylation of PR Ser-294 blocks PR Lys-388 sumoylation. SUMO-deficient mutant PR-B (K388R) thus provides a model receptor for the study of PR function in the context of high kinase activities. T47D cells stably expressing K388R PR-B exhibited increased ligand-independent proliferation and growth in soft agar relative to cells expressing wt PR-B or phospho-mutant (sumoylated) S294A PR-B. Expression of selected PR target genes (HB-EGF, IRS-1, and STC1) was significantly elevated in cells containing desumoylated (K388R) PR-B. Basal PR transcriptional activity occurred independently of progestins, was increased by activated CDK2, and attenuated by RU486. Notably, ChIP assays demonstrated that K388R PR-B and SRC1 were constitutively recruited to the STC1 promoter in the absence of progestin; PR Lys-388 sumoylation was required for HDAC3 recruitment. Knock-down of STC1 inhibited proliferation of cells expressing K388R PR-B. These data suggest a mechanism whereby phosphorylated, and thus desumoylated, PRs mediate increased expression of growth promoting genes. Our data explain why breast cancer models often remain insensitive to progestins, but are growth-inhibited by antiprogestins, and underscore the need to target PR-B and associated kinase activities as part of breast cancer therapy.

Original languageEnglish (US)
Pages (from-to)14287-14292
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number34
DOIs
StatePublished - Aug 25 2009

Keywords

  • HDAC
  • Phosphorylation
  • Sumoylation

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