Sphingosine kinase 1 activation by estrogen receptor α36 contributes to tamoxifen resistance in breast cancer

• DOI: 10.1194/jlr.m085191
• Publication Date: 2018-10-12T20:25:11Z
• Authors: Melissa A. Maczis; Michael Maceyka; Michael R. Waters; Jason Newton; Manjulata Singh; Madisyn F. Rigsby; Tia H. Turner; Mohammad A. Alzubi; J. Chuck Harrell; Sheldon Milstien; Sarah Spiegel
• Keywords: Fulvestrant; Sphingosine kinase 1; Estrogen receptor alpha

In breast cancer, 17β-estradiol (E2) plays critical roles mainly by binding to its canonical receptor, estrogen receptor (ER) α66, and eliciting genomic effects. E2 also triggers rapid, nongenomic responses. activates sphingosine kinase 1 (SphK1), increasing sphingosine-1-phosphate (S1P) that binds receptors, leading important cancer signaling. However, the responsible for SphK1 activation has not yet been identified. Here, we demonstrate in triple-negative cells, which lack ERα66 but express novel splice variant ERα36, ERα36 is E2-induced of formation secretion S1P dihydro-S1P, ligands S1PRs. Tamoxifen, first-line endocrine therapy an antagonist ERα66, agonist and, like E2, markedly increases S1P. A major problem with tamoxifen development acquired resistance. We found resistance correlated increased expression tamoxifen-resistant patient-derived xenografts, endocrine-resistant patients. Our data indicate targeting this axis may be a therapeutic option circumvent improve patient outcome.