Prolactin-Stat5 signaling in breast cancer is potently disrupted by acidosis within the tumor microenvironment. Breast Cancer Res 2013;15(5):R73
Date
09/06/2013Pubmed ID
24004716Pubmed Central ID
PMC3978581DOI
10.1186/bcr3467Scopus ID
2-s2.0-84883283477 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
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.
Author List
Yang N, Liu C, Peck AR, Girondo MA, Yanac AF, Tran TH, Utama FE, Tanaka T, Freydin B, Chervoneva I, Hyslop T, Kovatich AJ, Hooke JA, Shriver CD, Rui HMESH terms used to index this publication - Major topics in bold
AcidosisAnimals
Breast Neoplasms
Cell Line, Tumor
Cell Nucleus
Disease Models, Animal
Extracellular Space
Female
Glucose
Glucose Transporter Type 1
Glycolysis
Heterografts
Humans
Phosphorylation
Prolactin
Protein Transport
Receptors, Prolactin
STAT5 Transcription Factor
Signal Transduction
Tumor Microenvironment
