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

Yu Jin Lee,Dong-Young Noh,Pann-Ghill Suh,Seorim Park,Sung Ho Ryu,Kyun Heo,Kyeong Jin Shin,Soo-Ah Park,Kyeong Su Park,Young-Kyo Seo

doi:10.18632/oncotarget.12286

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.

Highlights

Breast cancer is the leading cause of cancer-related mortality in females worldwide [1]
Increased G-protein-coupled receptor 81 (GPR81) expression was correlated with the estrogen receptor (ER)-positive status of breast cancer patients (Supplementary Figure S1B), which suggests that GPR81 may comprise an important regulator or prognostic marker of breast cancer
In the tumor microenvironment, increased lactate levels significantly activated GPR81, which leads to the activation of cell survival signaling and the production of the angiogenic factor AREG to promote angiogenesis and cancer cell growth via phosphoinositide 3-OH kinase (PI3K)/Akt pathway

Summary

Introduction

Breast cancer is the leading cause of cancer-related mortality in females worldwide [1]. Our understanding of the molecular mechanisms of breast cancer has improved in the previous two decades; the prognosis and treatment of breast cancer, in advanced cases, has not been significantly improved [2, 3]. A more detailed understanding of the molecular mechanisms underlying the breast cancer progression will provide new insight into individual treatment of breast cancer. Abnormal expression of specific GPCRs on cell membranes stimulates the continual unregulated proliferation and triggers intracellular signal transductions that lead to the growth of cancer cells, induction of angiogenesis and metastasis. 50% of marketed pharmaceuticals target human GPCRs or their signaling pathways; a limited number of these receptors are used as cancer therapeutic targets [9, 10]. A tremendous amount of efforts have been made to so far aiming at exploiting therapeutic applications of the remaining family members, including more than 140 orphan GPCRs whose endogenous ligands or functions have yet to be unidentified [11]

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