title: ODAM inhibits RhoA-dependent invasion in breast cancer.
abstract: Odontogenic ameloblast-associated protein (ODAM) contributes to cell adhesion. In human cancer, ODAM is down-regulated, and the overexpression of ODAM results in a favourable prognosis; however, the molecular mechanisms underlying ODAM-mediated inhibition of cancer invasion and metastasis remain unclear. Here, we identify a critical role for ODAM in inducing cancer cell adhesion. ODAM induced RhoA activity and the expression of downstream factors, including Rho-associated kinase (ROCK). ODAM-mediated RhoA signalling resulted in actin filament rearrangement by activating PTEN and inhibiting the phosphorylation of AKT. When ODAM is overexpressed in MCF7 breast cancer cells and AGS gastric cancer cells that activate RhoA at high levels, it decreases motility, increases adhesion and inhibits the metastasis of MCF7 cells. Conversely, depletion of ODAM in cancer cells inhibits Rho GTPase activation, resulting in increased cancer migration and invasion. These results suggest that ODAM expression in cells maintains their adhesion, resulting in the prevention of their metastasis via the regulation of RhoA signalling in breast cancer cells. SIGNIFICANCE Breast cancer represents the first most frequent cancer, and the ratio of mortality is high in women. Of utmost importance for reducing risk by breast cancer are their anti-invasion mechanisms, particularly in the non-invasive cancer cells because metastasis is the principal cause of death among cancer patients. ODAM induced RhoA activity. ODAM-mediated RhoA signalling resulted in actin filament rearrangement, increased cell adhesion and inhibited the migration/invasion of MCF7 cells. These results suggest that ODAM expression maintains their adhesion, resulting in the prevention of their metastasis via the regulation of RhoA signalling in breast cancer cells.
authors.affiliation: Department of Oral Histology-Developmental Biology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Oral Histology-Developmental Biology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Han-Wool
authors.initials: HW
authors.lastname: Choung
authors.affiliation: Paik Institute Clinical Research, Inje University, Busan, Republic of Korea.
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Yang
authors.affiliation: Department of Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Yoon
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: In Ae
authors.initials: IA
authors.lastname: Park
authors.affiliation: Department of Oral Histology-Developmental Biology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Joo-Cheol
authors.initials: JC
authors.lastname: Park
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000682:Amyloid; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000682:Amyloid; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C480049:ODAM protein, human; C066737:RHOA protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020742:rhoA GTP-Binding Protein
keywords: ODAM; RhoA signalling pathway; cancer invasion; cell adhesion