Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling

Oncogene. 2012 Jun 21;31(25):3086-97. doi: 10.1038/onc.2011.476. Epub 2011 Oct 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • Female
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / pathology*
  • Neoplasm Proteins / metabolism*
  • Rho Guanine Nucleotide Exchange Factors
  • Securin
  • Signal Transduction*
  • rhoA GTP-Binding Protein / metabolism*


  • ARHGEF2 protein, human
  • Guanine Nucleotide Exchange Factors
  • Neoplasm Proteins
  • Rho Guanine Nucleotide Exchange Factors
  • Securin
  • RHOA protein, human
  • rhoA GTP-Binding Protein