HER2 regulation of peroxisome proliferator-activated receptor γ (PPARγ) expression and sensitivity of breast cancer cells to PPARγ ligand therapy

Zhibo Yang, Rozita Bagheri-Yarmand, Seetharaman Balasenthil, Gabriel Hortobagyi, Aysegul A. Sahin, Christopher J. Barnes, Rakesh Kumar

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Induction of terminal differentiation of cancer cells is an evolving novel therapeutic approach, and accordingly, peroxisome proliferator-activated receptor γ (PPARγ), a ligand-stimulated transcription factor with differentiation-promoting activity and overexpressed in a variety of cancers, has emerged as one of the promising therapeutic targets. Because c-erbB family growth factor receptor 2 (HER2) overexpression is one of the most recognizable molecular dysfunctions in breast tumors, in the studies presented here, we explored the effect of HER2 overexpression on the status of PPARγ expression and on the sensitivity of breast cancer cells to PPARγ-ligand troglitazone-induced growth inhibition. We show that HER2 overexpression in MCF7 breast cancer cells enhanced the expression of PPARγ-mRNA and -protein. Furthermore, PPARγ expression was dramatically increased in 11 of 16 breast tumors as compared with the adjacent normal tissue. In addition, HER2 up-regulation resulted in a partial inhibition of transcriptional activity of the endogenous PPARγ, stimulation to differentiation, and resistance to troglitazone-mediated inhibition of anchorage-independent growth of breast cancer cells. Conversely, down-regulation of HER2 by anti-HER2 monoclonal antibody Herceptin led to a decreased level of PPARγ protein and sensitization of breast cancer cells to the inhibitory effects of troglitazone. In summary, these findings show for the first time that HER2 up-regulates PPARγ expression and modulates the sensitivity of breast cancer cells to PPARγ ligand therapy.

Original languageEnglish (US)
Pages (from-to)3198-3203
Number of pages6
JournalClinical Cancer Research
Volume9
Issue number8
StatePublished - Aug 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'HER2 regulation of peroxisome proliferator-activated receptor γ (PPARγ) expression and sensitivity of breast cancer cells to PPARγ ligand therapy'. Together they form a unique fingerprint.

  • Cite this

    Yang, Z., Bagheri-Yarmand, R., Balasenthil, S., Hortobagyi, G., Sahin, A. A., Barnes, C. J., & Kumar, R. (2003). HER2 regulation of peroxisome proliferator-activated receptor γ (PPARγ) expression and sensitivity of breast cancer cells to PPARγ ligand therapy. Clinical Cancer Research, 9(8), 3198-3203.