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J Lipid Res. 2018 Dec;59(12):2297-2307. doi: 10.1194/jlr.M085191. Epub 2018 Oct 12.

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

Author information

1
Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of Medicine, Richmond, VA 23298.
2
Department of Pathology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298.
3
Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of Medicine, Richmond, VA 23298 sarah.spiegel@vcuhealth.org.

Abstract

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

KEYWORDS:

estradiol; estrogen receptor-α; sphingosine-1-phosphate; splice variant

PMID:
30315000
PMCID:
PMC6277156
[Available on 2019-12-01]
DOI:
10.1194/jlr.M085191

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