title: BMP-6 inhibits cell proliferation by targeting microRNA-192 in breast cancer.
abstract: Although bone morphogenetic protein-6 (BMP-6) has been identified as a tumor suppressor associated with breast cancer differentiation and metastasis, the potential roles of BMP-6 in regulating cell cycle progression have not been fully examined. In the present study, we provide the novel finding that induction of BMP-6 in MDA-MB-231 breast cancer cells significantly inhibits cell proliferation by decreasing the number of cells in S phase of the cell cycle, resulting in inhibition of tumorigenesis in a nude mouse xenograft model. Further investigation indicated that BMP-6 up-regulates the expression of microRNA-192 (miR-192) in MDA-MB-231 cells. Elevated expression of miR-192 caused cell growth arrest, which is similar to the effect of BMP-6 induction. Importantly, depletion of endogenous miR-192 by miRNA inhibition significantly attenuated BMP-6-mediated repression of cell cycle progression. In breast cancer tissue, miR-192 expression is significantly down-regulated in tumor samples and positively correlates with the expression of BMP-6, demonstrating the inhibitory effect of BMP-6 on cell proliferation through miR-192 regulation. Additionally, using the RT(2) Profiler PCR Array, retinoblastoma 1 (RB1) was identified as a direct target of the BMP-6/miR-192 pathway in regulating cell proliferation in breast cancer. In conclusion, we have identified an important role for BMP-6/miR-192 signaling in the regulation of cell cycle progression in breast cancer. Furthermore, BMP-6/miR-192 was expressed at low levels in breast cancer specimens, indicating that this pathway might represent a promising therapeutic target for breast cancer treatment.
authors.affiliation: Medical College of Nankai University, Tianjin, China; College of Life Sciences, Hebei United University, Tangshan, Hebei, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Hu
authors.forename: Xiangzhi
authors.initials: X
authors.lastname: Meng
authors.forename: Qi
authors.initials: Q
authors.lastname: Tong
authors.forename: Lin
authors.initials: L
authors.lastname: Liang
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Tianhui
authors.initials: T
authors.lastname: Zhu
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; C546783:MIRN192 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D008156:Luciferases
keywords: Bone morphogenetic protein-6; Breast cancer; Cell proliferation; MicroRNA-192; Retinoblastoma 1