Differential expression and function of the endogenous lactate receptor, GPR81, in ER��-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 triplenegative 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 onlycontaining 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.

Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk

“…The study concluded that MCT1 and hypoxia are mutually exclusive in glycolytic tumors, and MCT1 inhibition induced lung carcinoma cell necrosis and sensitizes cells to irradiation in vivo [25]. One breast cancer study found that endogenous lactate receptor G protein-coupled receptor 81 (GPR81) mRNA expression is elevated in clinical estrogen receptor alpha-positive (ERα + ) and human epidermal receptor-growth factor 2-positive (Her2 + ) breast cancer versus triple-negative breast cancer (TNBC) and benign tissue samples [139]. In vitro, GPR81 regulates MCT1 expression and lactate uptake in MCF-7 breast epithelial breast cancer cells and is responsible for cancer-cell proliferation and survival when lactate is the main nutrient source [139].…”

Lactate Metabolism and Immune Modulation in Breast Cancer: A Focused Review on Triple Negative Breast Tumors

“…Furthermore, the lactate sensing G-protein-coupled receptor 81 (GPR81), also known as hydrocarboxylic acid receptor 1 (HCAR1) has been implicated in an autocrine feedback loop that regulates MCT1 and/or MCT4 expression and their chaperone CD147 (68-70). GPR81 is highly expressed in many tumor types including breast cancer, in particular hormone receptor positive breast cancers where it is associated with improved overall survival and lower risk of distant metastasis (69,71,72). Silencing of GPR81 in hormone receptor positive breast tumor cells reduced the expression of specifically MCT1 but not of MCT2 or MCT4, resulting in decreased lactate uptake, extracellular acidification, and inhibition of tumor cell proliferation and survival (69).…”

“…GPR81 is highly expressed in many tumor types including breast cancer, in particular hormone receptor positive breast cancers where it is associated with improved overall survival and lower risk of distant metastasis (69,71,72). Silencing of GPR81 in hormone receptor positive breast tumor cells reduced the expression of specifically MCT1 but not of MCT2 or MCT4, resulting in decreased lactate uptake, extracellular acidification, and inhibition of tumor cell proliferation and survival (69). Hence, GPR81 may support the OXPHOS phenotype in these breast tumors by sensing and regulating influx of extracellular lactate.…”