Differential expression and function of the endogenous lactate receptor, GPR81, in ERα-positive/HER2-positive epithelial vs. post-EMT triple-negative mesenchymal breast cancer cells

Abstract

Aim: Lactate can signal through the endogenous lactate receptor, GPR81, which is expressed in some cancers. Lactate metabolism is altered by the metastasis-promoting process of epithelial-mesenchymal transition (EMT). This study examined the expression and function of GPR81 in breast cancer samples, and in receptor-positive epithelial vs. triple-negative post-EMT mesenchymal breast cancer cells.

Methods: GPR81 mRNA expression was examined by breast cancer microarray, and by a Kaplan-Meier survival curve. Using 3-dimensional culture conditions, GPR81 mRNA expression in epithelial and mesenchymal breast cancer cell lines was measured by qRT-PCR. GPR81 siRNA was used to assess the role of GPR81, alone or in conjunction with tamoxifen, in the regulation of MCT1 and MCT4 lactate transporters, intracellular lactate, and cell proliferation and survival.

Results: GPR81 mRNA levels were elevated in receptor-positive breast cancer, relative to non-tumor and triple-negative samples, and correlated with increased survival. GPR81 expression was elevated in the two epithelial breast cancer cell lines vs. the corresponding post-EMT mesenchymal cell lines. GPR81 knock-down in epithelial MCF7 cells caused: 1, selectively lower mRNA and protein expression of the MCT1 transporter, but not MCT2 or MCT4 transporters; 2, lower levels of intracellular lactate; and 3, decreased proliferation and survival in lactate only-containing conditions. GPR81 siRNA plus tamoxifen displayed additive suppressive effects on MCT1 expression and cell viability.

Conclusion: GPR81 promotes the ability of epithelial breast cancer cells to import lactate for energy use. As such, GPR81 represents a potential target for treatment of hormone-positive breast cancer cells, and may be prognostic for higher grade breast cancer.

Keywords

GPR81 / lactate metabolism / MCT transporters / MCT1 / tamoxifen

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