title: Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling.
abstract: Human pituitary tumour-transforming gene 1 (hPTTG1) is an oncogenic transcription factor that is overexpressed in many tumour types, especially tumours with metastatic abilities. However, how hPTTG1 overexpression drives metastasis is not yet clear. As a transcription factor, hPTTG1 may promote metastasis by activating target genes that are involved in the metastatic process. Here, we showed that Rho guanine nucleotide exchange factor-H1 (GEF-H1) was transcriptionally activated by hPTTG1, thereby promoting breast cancer metastasis. Luciferase reporter analyses and chromatin immunoprecipitation (ChIP) assays showed that hPTTG1 directly bound and activated the GEF-H1 gene promoter. In this study, RNA interference-mediated knockdown of hPTTG1 in highly metastatic breast tumour cells decreased GEF-H1 expression and RhoA activation, thereby reducing cell motility and invasion, and interfering with cytoskeletal remodelling in vitro, and impairing the tumour metastasis in vivo. The restoration of GEF-H1 expression in hPTTG1-knockdown cells rescued the hPTTG1-knockdown effects on cytoskeletal changes in vitro and tumour metastasis in vivo. Conversely, ectopic expression of hPTTG1 in non-metastatic breast tumour cells induced cytoskeletal rearrangements, and allowed these cells to metastasise in a mouse model by orthotopic implantation. In human tumour samples, hPTTG1 expression was also correlated to GEF-H1 expression in aggressive breast carcinoma. Altogether, these findings definitively establish a role for hPTTG1 in activating the GEF-H1/RhoA pathway as a newly identified mechanism in breast cancer metastasis.
authors: Institute of Medical Science, Tzu-Chi University, Hualien, Taiwan.
authors: Y C
authors: YC
authors: Liao
authors: J W
authors: JW
authors: Ruan
authors: I
authors: I
authors: Lua
authors: M H
authors: MH
authors: Li
authors: W L
authors: WL
authors: Chen
authors: J R Y
authors: JR
authors: Wang
authors: R H
authors: RH
authors: Kao
authors: J H
authors: JH
authors: Chen
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D064249:Securin; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C577356:ARHGEF2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D064249:Securin; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein