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

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 pati...

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Bibliographic Details
Published in:Oncotarget 2016-10, Vol.7 (43), p.70898-70911
Main Authors: Lee, Yu Jin, Shin, Kyeong Jin, Park, Soo-Ah, Park, Kyeong Su, Park, Seorim, Heo, Kyun, Seo, Young-Kyo, Noh, Dong-Young, Ryu, Sung Ho, Suh, Pann-Ghill
Format: Article
Language:English
Subjects:
Amphiregulin - metabolism
Animals
Apoptosis
Breast - blood supply
Breast - pathology
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Proliferation
Cell Separation - methods
Cyclic AMP Response Element-Binding Protein - metabolism
Female
Flow Cytometry
Gene Knockdown Techniques
Humans
Lactic Acid - metabolism
Mice
Mice, Nude
Neovascularization, Pathologic - pathology
Phosphatidylinositol 3-Kinases - metabolism
Primary Cell Culture
Proto-Oncogene Proteins c-akt - metabolism
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Research Paper
RNA Interference
RNA, Small Interfering - metabolism
Signal Transduction
Tumor Microenvironment
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.12286