Reciprocal fine-tuning of progesterone and prolactin-regulated gene expression in breast cancer cells

Sean M. Holloran, Bakhtiyor Nosirov, Katherine R. Walter, Gloria M. Trinca, Zhao Lai, Victor X. Jin, Christy R. Hagan

Research output: Contribution to journalArticle

Abstract

Progesterone and prolactin are two key hormones involved in development and remodeling of the mammary gland. As such, both hormones have been linked to breast cancer. Despite the overlap between biological processes ascribed to these two hormones, little is known about how co-expression of both hormones affects their individual actions. Progesterone and prolactin exert many of their effects on the mammary gland through activation of gene expression, either directly (progesterone, binding to the progesterone receptor [PR]) or indirectly (multiple transcription factors being activated downstream of prolactin, most notably STAT5). Using RNA-seq in T47D breast cancer cells, we characterized the gene expression programs regulated by progestin and prolactin, either alone or in combination. We found significant crosstalk and fine-tuning between the transcriptional programs executed by each hormone independently and in combination. We divided and characterized the transcriptional programs into four broad categories. All crosstalk/fine-tuning shown to be modulated by progesterone was dependent upon the expression of PR. Moreover, PR was recruited to enhancer regions of all regulated genes. Interestingly, despite the canonical role for STAT5 in transducing prolactin-signaling in the normal and lactating mammary gland, very few of the prolactin-regulated transcriptional programs fine-tuned by progesterone in this breast cancer cell line model system were in fact dependent upon STAT5. Cumulatively, these data suggest that the interplay of progesterone and prolactin in breast cancer impacts gene expression in a more complex and nuanced manner than previously thought, and likely through different transcriptional regulators than those observed in the normal mammary gland. Studying gene regulation when both hormones are present is most clinically relevant, particularly in the context of breast cancer.

Original languageEnglish (US)
Article number110859
JournalMolecular and Cellular Endocrinology
Volume511
DOIs
StatePublished - Jul 1 2020

Keywords

  • Breast cancer
  • Gene expression
  • Progesterone receptor
  • Prolactin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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