G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion

Abstract

G-protein-coupled receptor 81 (GPR81) functions as a receptor for lactate and plays an important role in the regulation of anti-lipolytic effects in adipocytes. However, to data, a role for GPR81 in the tumor microenvironment has not been clearly defined. Here, GPR81 expression in breast cancer patients and several breast cancer cell lines was significantly increased compared with normal mammary tissues and cells. GPR81 knockdown resulted in impaired breast cancer growth and led to apoptosis both in vitro and in vivo. Furthermore, the inhibition of GPR81 signaling suppressed angiogenesis through a phosphoinositide 3-OH kinase (PI3K)/Akt-cAMP response element binding protein (CREB) pathway, which led to decreased production of the pro-angiogenic mediator amphiregulin (AREG). Overall, these findings identify GPR81 as a tumor-promoting receptor in breast cancer progression and suggest a novel mechanism that regulates GPR81-dependent activation of the PI3K/Akt signaling axis in tumor microenvironment.

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

“…We also observed a significant association between GPR81 overexpression with ERα-positive and human epidermal growth HER2 positive human breast cancer tissues as opposed to triple negative breast cancer. This is consistent with previous observations that ERα-positive breast cancer tissues overexpressed GPR81 [25] . In addition, GPR81 was expressed at higher levels in the first three stages of breast cancer (Stage I, II and III) as compared to Stage IV, and GPR81 expression correlated with better overall survival of breast cancer patients.…”

“…More recently, GPR81 expression has been found to be upregulated in several types of cancer, including pancreatic, colon, liver, breast, lung and cervical cancers, and in several cases high GPR81 expression was associated with tumor growth, chemoresistance and metastasis [25][26][27][28] . It should also be noted that previous studies indicate that lactate activates GPR81 in the millimolar range (1-5 mmol/L), and in human breast cancer tissues lactate was found to be at concentrations as high as 8 mmol/L [14] , suggesting that GPR81 and downstream signaling pathways could be constantly activated by lactate in the breast tumor microenvironment.…”

“…In contrast, EMT induction and transformation of epithelial breast cancer cells into triple negative mesenchymal cancer cells was associated with significantly reduced expression of GPR81. Lee et al [25] reported that GPR81 expression is significantly increased in breast cancer patients compared to normal mammary tissues. We also observed a significant association between GPR81 overexpression with ERα-positive and human epidermal growth HER2 positive human breast cancer tissues as opposed to triple negative breast cancer.…”

“…GPR81 activation by lactate decreases cAMP production, which ultimately reduces lipolysis [24] . Recently GPR81 has been shown to be upregulated in several cancers (pancreas, colon, liver, breast, cervix) and its expression levels associated with tumor growth and metastasis [25][26][27][28][29] . In this current study, we examined GPR81 expression in the context of EMT in breast cancer.…”

Cell-surface G-protein-coupled receptors for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer

“…Interestingly, the expression of the lactate transporters MCT1 and MCT4 is modulated by GPR81; exposure of pancreatic cancer cells to lactate in extracellular medium increases the expression of these two transporters, thus facilitating release of lactate from cancer cells [70]. GPR81 activation also promotes a malignant phenotype in cancer cells by enhancing angiogenesis via increased secretion of the pro-angiogenic factor amphiregulin [72]. This process involves the PI3K/AKT pathway coupled to decreased cellular levels of cAMP.…”