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 Partridge, Chellakkan S. Benson, Mayuranathan Thiyagaraj, Narasimhan Srinivasan, Nagarajan Selvamurugan

Research output: Contribution to journalArticle

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

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Activating Transcription Factor 3
Transforming Growth Factors
Genes
Cells
Breast Neoplasms
Cyclin A1
Matrix Metalloproteinases
Matrix Metalloproteinase 13
Small Interfering RNA
Neoplasm Metastasis
cdc Genes
Chromatin Immunoprecipitation
Cell proliferation
RNA Interference
Osteogenesis
Chromatin
Tumors
Bone
Breast

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Transforming growth factor-β1 regulation of ATF-3 and identification of ATF-3 target genes in breast cancer cells. / Kwok, Sukyee; Rittling, Susan R.; Partridge, Nicola; Benson, Chellakkan S.; Thiyagaraj, Mayuranathan; Srinivasan, Narasimhan; Selvamurugan, Nagarajan.

In: Journal of Cellular Biochemistry, Vol. 108, No. 2, 01.10.2009, p. 408-414.

Research output: Contribution to journalArticle

Kwok, Sukyee ; Rittling, Susan R. ; Partridge, Nicola ; Benson, Chellakkan S. ; Thiyagaraj, Mayuranathan ; Srinivasan, Narasimhan ; Selvamurugan, Nagarajan. / Transforming growth factor-β1 regulation of ATF-3 and identification of ATF-3 target genes in breast cancer cells. In: Journal of Cellular Biochemistry. 2009 ; Vol. 108, No. 2. pp. 408-414.
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