title: Prolactin-Stat5 signaling in breast cancer is potently disrupted by acidosis within the tumor microenvironment.
abstract: BACKGROUND
  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.
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.forename: Chengbao
authors.initials: C
authors.lastname: Liu
authors.forename: Amy R
authors.initials: AR
authors.lastname: Peck
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Girondo
authors.forename: Alicia F
authors.initials: AF
authors.lastname: Yanac
authors.forename: Thai H
authors.initials: TH
authors.lastname: Tran
authors.forename: Fransiscus E
authors.initials: FE
authors.lastname: Utama
authors.forename: Takemi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Boris
authors.initials: B
authors.lastname: Freydin
authors.forename: Inna
authors.initials: I
authors.lastname: Chervoneva
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kovatich
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hooke
authors.forename: Craig D
authors.initials: CD
authors.lastname: Shriver
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis; D064593:Heterografts; D006801:Humans; D010766:Phosphorylation; D011388:Prolactin / Q000378:metabolism*; D021381:Protein Transport; D011981:Receptors, Prolactin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D051272:Glucose Transporter Type 1; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D011388:Prolactin; D005947:Glucose