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 p...

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Autores principales:	Alicia E. Woock, Jacqueline M. Grible, Amy L. Olex, J. Chuck Harrell, Patricija Zot, Michael Idowu, Charles V. Clevenger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ac88965986da4b14922876d81cbc4694
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spelling	oai:doaj.org-article:ac88965986da4b14922876d81cbc46942021-12-02T16:10:38ZSerine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer10.1038/s41598-021-92830-82045-2322https://doaj.org/article/ac88965986da4b14922876d81cbc46942021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92830-8https://doaj.org/toc/2045-2322Abstract 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.Alicia E. WoockJacqueline M. GribleAmy L. OlexJ. Chuck HarrellPatricija ZotMichael IdowuCharles V. ClevengerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alicia E. Woock Jacqueline M. Grible Amy L. Olex J. Chuck Harrell Patricija Zot Michael Idowu Charles V. Clevenger Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer
description	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.
format	article
author	Alicia E. Woock Jacqueline M. Grible Amy L. Olex J. Chuck Harrell Patricija Zot Michael Idowu Charles V. Clevenger
author_facet	Alicia E. Woock Jacqueline M. Grible Amy L. Olex J. Chuck Harrell Patricija Zot Michael Idowu Charles V. Clevenger
author_sort	Alicia E. Woock
title	Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer
title_short	Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer
title_full	Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer
title_fullStr	Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer
title_full_unstemmed	Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer
title_sort	serine residues 726 and 780 have nonredundant roles regulating stat5a activity in luminal breast cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ac88965986da4b14922876d81cbc4694
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Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer

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