title: Novel role of cannabinoid receptor 2 in inhibiting EGF/EGFR and IGF-I/IGF-IR pathways in breast cancer.
abstract: Breast cancer is the second leading cause of cancer deaths among women. Cannabinoid receptor 2 (CNR2 or CB2) is an integral part of the endocannabinoid system. Although CNR2 is highly expressed in the breast cancer tissues as well as breast cancer cell lines, its functional role in breast tumorigenesis is not well understood. We observed that estrogen receptor-α negative (ERα-) breast cancer cells highly express epidermal growth factor receptor (EGFR) as well as insulin-like growth factor-I receptor (IGF-IR). We also observed IGF-IR upregulation in ERα+ breast cancer cells. In addition, we found that higher CNR2 expression correlates with better recurrence free survival in ERα- and ERα+ breast cancer patients. Therefore, we analyzed the role of CNR2 specific agonist (JWH-015) on EGF and/or IGF-I-induced tumorigenic events in ERα- and ERα+ breast cancers. Our studies showed that CNR2 activation inhibited EGF and IGF-I-induced migration and invasion of ERα+ and ERα- breast cancer cells. At the molecular level, JWH-015 inhibited EGFR and IGF-IR activation and their downstream targets STAT3, AKT, ERK, NF-kB and matrix metalloproteinases (MMPs). In vivo studies showed that JWH-015 significantly reduced breast cancer growth in ERα+ and ERα- breast cancer mouse models. Furthermore, we found that the tumors derived from JWH-015-treated mice showed reduced activation of EGFR and IGF-IR and their downstream targets. In conclusion, we show that CNR2 activation suppresses breast cancer through novel mechanisms by inhibiting EGF/EGFR and IGF-I/IGF-IR signaling axes.
authors.affiliation: Department of Pathology and The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.|Department of Pharmacology, Pharmacy School, Helwan University, Helwan, Egypt.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Elbaz
authors.affiliation: Department of Pathology and The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Ahirwar
authors.affiliation: Department of Pathology and The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
authors.forename: Janani
authors.initials: J
authors.lastname: Ravi
authors.affiliation: Department of Pathology and The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
authors.forename: Mohd W
authors.initials: MW
authors.lastname: Nasser
authors.affiliation: Department of Pathology and The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ganju
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D011379:Prognosis; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D007211:Indoles; D043885:Receptor, Cannabinoid, CB2; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; C402944:JHW 015
keywords: CNR2; EGFR; IGF-IR