Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer.

Abstract

In breast cancer, prolactin-induced activation of the transcription factor STAT5a results from the phosphorylation of STAT5a tyrosine residue 694. However, its role in mammary oncogenesis remains an unsettled debate as STAT5a exhibits functional dichotomy with both pro-differentiative and pro-proliferative target genes. Phosphorylation of STAT5a serine residues, S726 and S780, may regulate STAT5a in such a way to underlie this duality. Given hematopoiesis studies showing phospho-serine STAT5a as necessary for transformation, we hypothesized that serine phosphorylation regulates STAT5a activity to contribute to its role in mammary oncogenesis, specifically in luminal breast cancer. Here, phosphorylation of S726-, S780-, and Y694-STAT5a in response to prolactin in MCF7 luminal breast cancer cells was investigated with STAT5a knockdown and rescue with Y694F-, S726A-, or S780A-STAT5a, where the phospho-sites were mutated. RNA-sequencing and subsequent Ingenuity Pathway Analysis predicted that loss of each phospho-site differentially affected both prolactin-induced gene expression as well as functional pathways of breast cancer (e.g. cell survival, proliferation, and colony formation). In vitro studies of anchorage-independent growth and proliferation confirmed distinct phenotypes: whereas S780A-STAT5a decreased clonogenicity, S726A-STAT5a decreased proliferation in response to prolactin compared to wild type STAT5a. Collectively, these studies provide novel insights into STAT5a activation in breast cancer pathogenesis.

• Authors: Alicia E Woock, Jacqueline M Grible, Amy L Olex, J Chuck Harrell, Patricija Zot, Michael Idowu, Charles V Clevenger
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 13506 (06 29 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34188118 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Neoplasm Proteins
• STAT5 Transcription Factor
• STAT5A protein, human
• Tumor Suppressor Proteins
• Serine
• Prolactin

Topics

• Breast Neoplasms (genetics, metabolism, pathology)
• Carcinogenesis (genetics, metabolism, pathology)
• Female
• Humans
• MCF-7 Cells
• Neoplasm Proteins (genetics, metabolism)
• Phosphorylation (drug effects, genetics)
• Prolactin (pharmacology)
• STAT5 Transcription Factor (genetics, metabolism)
• Serine (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)