Prolactin-Stat5 signaling in breast cancer is potently disrupted by acidosis within the tumor microenvironment
1 Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA
2 Department of Pathology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA
3 Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA
4 Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, 130 South 9th Street, Philadelphia, PA 19107, USA
5 Department of Pharmacology and Experimental Therapeutics, Division of Biostatistics, Thomas Jefferson University, 1015 Chestnut Street, Philadelphia, PA 19107, USA
6 MDR Global Systems, LLC, 425 Park Place, Windber, PA 15963, USA
7 Department of Surgery, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20814, USA
8 Department of Cancer Biology, Thomas Jefferson University, 233 South 10th Street, BLSB 330, Philadelphia, PA 19107, USA
Breast Cancer Research 2013, 15:R73 doi:10.1186/bcr3467Published: 3 September 2013
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.
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.
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.
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.