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Breast Cancer Research
Published in: Breast Cancer Research 5/2013

Open Access 01-10-2013 | Research article

Prolactin-Stat5 signaling in breast cancer is potently disrupted by acidosis within the tumor microenvironment

Authors: Ning Yang, Chengbao Liu, Amy R Peck, Melanie A Girondo, Alicia F Yanac, Thai H Tran, Fransiscus E Utama, Takemi Tanaka, Boris Freydin, Inna Chervoneva, Terry Hyslop, Albert J Kovatich, Jeffrey A Hooke, Craig D Shriver, Hallgeir Rui

Published in: Breast Cancer Research | Issue 5/2013

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Abstract

Introduction

Emerging evidence in estrogen receptor-positive breast cancer supports the notion that prolactin-Stat5 signaling promotes survival and maintenance of differentiated luminal cells, and loss of nuclear tyrosine phosphorylated Stat5 (Nuc-pYStat5) in clinical breast cancer is associated with increased risk of antiestrogen therapy failure. However, the molecular mechanisms underlying loss of Nuc-pYStat5 in breast cancer remain poorly defined.

Methods

We investigated whether moderate extracellular acidosis of pH 6.5 to 6.9 frequently observed in breast cancer inhibits prolactin-Stat5 signaling, using in vitro and in vivo experimental approaches combined with quantitative immunofluorescence protein analyses to interrogate archival breast cancer specimens.

Results

Moderate acidosis at pH 6.8 potently disrupted signaling by receptors for prolactin but not epidermal growth factor, oncostatin M, IGF1, FGF or growth hormone. In breast cancer specimens there was mutually exclusive expression of Nuc-pYStat5 and GLUT1, a glucose transporter upregulated in glycolysis-dependent carcinoma cells and an indirect marker of lactacidosis. Mutually exclusive expression of GLUT1 and Nuc-pYStat5 occurred globally or regionally within tumors, consistent with global or regional acidosis. All prolactin-induced signals and transcripts were suppressed by acidosis, and the acidosis effect was rapid and immediately reversible, supporting a mechanism of acidosis disruption of prolactin binding to receptor. T47D breast cancer xenotransplants in mice displayed variable acidosis (pH 6.5 to 6.9) and tumor regions with elevated GLUT1 displayed resistance to exogenous prolactin despite unaltered levels of prolactin receptors and Stat5.

Conclusions

Moderate extracellular acidosis effectively blocks prolactin signaling in breast cancer. We propose that acidosis-induced prolactin resistance represents a previously unrecognized mechanism by which breast cancer cells may escape homeostatic control.
Appendix
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Metadata
Title
Prolactin-Stat5 signaling in breast cancer is potently disrupted by acidosis within the tumor microenvironment
Authors
Ning Yang
Chengbao Liu
Amy R Peck
Melanie A Girondo
Alicia F Yanac
Thai H Tran
Fransiscus E Utama
Takemi Tanaka
Boris Freydin
Inna Chervoneva
Terry Hyslop
Albert J Kovatich
Jeffrey A Hooke
Craig D Shriver
Hallgeir Rui
Publication date
01-10-2013
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2013
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3467

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