Transforming growth factor-β1 regulation of ATF-3 and identification of ATF-3 target genes in breast cancer cells

Sukyee Kwok, Susan R. Rittling, Nicola C. Partridge, Chellakkan S. Benson, Mayuranathan Thiyagaraj, Narasimhan Srinivasan, Nagarajan Selvamurugan

Research output: Contribution to journalArticlepeer-review

Abstract

Transforming growth factor-β1 (TGF-β1) is a crucial molecule for stimulation of breast cancer invasion and formation of bone metastases. The molecular mechanisms of how TGF-β1 mediates these effects have yet to be completely determined. We have found that activating transcription factor-3 (ATF-3) is strongly stimulated and its level is sustained by TGF-β1 in highly invasive and metastatic human breast cancer (MDA-MB231) and in mouse mammary pad tumor cells (r3T). ATF-3 is also overexpressed in human primary breast cancer tissue. Overexpression of ATF-3 increased normal human mammary epithelial cell number and DNA synthesis suggesting a role for ATF-3 in cell proliferation. The functional role of ATF-3 in breast cancer progression was determined by the RNA interference technique. Knockdown of ATF-3 by ATF-3 shRNA in MDA-MB231 cells decreased expression of cell cycle gene, cyclin A1 in MDA-MB231 cells. ATF-3 shRNA also decreased expression of an invasive and metastatic gene, matrix metalloproteinase-13 (MMP-13; collagenase-3) in these cells. Chromatin immunoprecipitation experiments identified the direct physical interaction of ATF-3 protein on the human MMP-13 promoter. Thus, the dysregulation of ATF-3 by TGF-β1 is likely to activate cyclin A1 and MMP-13 genes in breast cancer cells and that would be key to the subsequent cancer cell invasion and metastasis.

Original languageEnglish (US)
Pages (from-to)408-414
Number of pages7
JournalJournal of Cellular Biochemistry
Volume108
Issue number2
DOIs
StatePublished - Oct 1 2009

Keywords

  • ATF-3
  • Cyclin A1
  • MMP-13
  • TGF-B

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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