title: 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.
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: Kyeong Jin
authors.initials: KJ
authors.lastname: Shin
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: Soo-Ah
authors.initials: SA
authors.lastname: Park
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: Kyeong Su
authors.initials: KS
authors.lastname: Park
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: Seorim
authors.initials: S
authors.lastname: Park
authors.affiliation: New Experimental Therapeutics Branch, Division of Convergence Technology, National Cancer Center, Goyang-si, Republic of Korea.
authors.forename: Kyun
authors.initials: K
authors.lastname: Heo
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: Young-Kyo
authors.initials: YK
authors.lastname: Seo
authors.affiliation: Department of Surgery, Seoul National University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
authors.affiliation: Department of Life Science, Pohang University of Science and Technology (POSTECH), San31, Hyoja Dong, Pohang, Republic of Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
mesh_terms: D066258:Amphiregulin / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001940:Breast / Q000098:blood supply / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation / Q000379:methods; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D066258:Amphiregulin; D017362:Cyclic AMP Response Element-Binding Protein; D019344:Lactic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C587848:AREG protein, human; C533610:HCAR1 protein, human
keywords: Akt; GPR81; amphiregulin; angiogenesis; breast cancer