PMID- 27765922 OWN - NLM STAT- MEDLINE DCOM- 20180223 LR - 20210211 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 7 IP - 43 DP - 2016 Oct 25 TI - G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion. PG - 70898-70911 LID - 10.18632/oncotarget.12286 [doi] AB - 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. FAU - Lee, Yu Jin AU - Lee YJ AD - School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea. FAU - Shin, Kyeong Jin AU - Shin KJ AD - School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea. FAU - Park, Soo-Ah AU - Park SA AD - School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea. FAU - Park, Kyeong Su AU - Park KS AD - School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea. FAU - Park, Seorim AU - Park S AD - School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea. FAU - Heo, Kyun AU - Heo K AD - New Experimental Therapeutics Branch, Division of Convergence Technology, National Cancer Center, Goyang-si, Republic of Korea. FAU - Seo, Young-Kyo AU - Seo YK AD - School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea. FAU - Noh, Dong-Young AU - Noh DY AD - Department of Surgery, Seoul National University, College of Medicine, Seoul, Republic of Korea. FAU - Ryu, Sung Ho AU - Ryu SH AD - Department of Life Science, Pohang University of Science and Technology (POSTECH), San31, Hyoja Dong, Pohang, Republic of Korea. FAU - Suh, Pann-Ghill AU - Suh PG AD - School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea. LA - eng PT - Journal Article PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (HCAR1 protein, human) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, G-Protein-Coupled) RN - 33X04XA5AT (Lactic Acid) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Amphiregulin/*metabolism MH - Animals MH - Apoptosis MH - Breast/blood supply/pathology MH - Breast Neoplasms/*pathology MH - Cell Line, Tumor MH - Cell Proliferation MH - Cell Separation/methods MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Female MH - Flow Cytometry MH - Gene Knockdown Techniques MH - Humans MH - Lactic Acid/metabolism MH - Mice MH - Mice, Nude MH - Neovascularization, Pathologic/*pathology MH - Phosphatidylinositol 3-Kinases/metabolism MH - Primary Cell Culture MH - Proto-Oncogene Proteins c-akt/metabolism MH - RNA Interference MH - RNA, Small Interfering/metabolism MH - Receptors, G-Protein-Coupled/genetics/*metabolism MH - Signal Transduction MH - *Tumor Microenvironment MH - Xenograft Model Antitumor Assays PMC - PMC5342597 OTO - NOTNLM OT - Akt OT - GPR81 OT - amphiregulin OT - angiogenesis OT - breast cancer COIS- CONFLICTS OF INTEREST The authors declare no conflict of interest. EDAT- 2016/10/22 06:00 MHDA- 2018/02/24 06:00 PMCR- 2016/10/25 CRDT- 2016/10/22 06:00 PHST- 2016/04/20 00:00 [received] PHST- 2016/09/02 00:00 [accepted] PHST- 2016/10/22 06:00 [pubmed] PHST- 2018/02/24 06:00 [medline] PHST- 2016/10/22 06:00 [entrez] PHST- 2016/10/25 00:00 [pmc-release] AID - 12286 [pii] AID - 10.18632/oncotarget.12286 [doi] PST - ppublish SO - Oncotarget. 2016 Oct 25;7(43):70898-70911. doi: 10.18632/oncotarget.12286.