TGF-β1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer

Shinako Araki, Jacob A. Eitel, Christopher N. Batuello, Khadijeh Bijangi-Vishehsaraei, Xian Jin Xie, David Danielpour, Karen E. Pollok, David A. Boothman, Lindsey D. Mayo

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

The E3 ubiquitin ligase human murine double minute (HDM2) is overexpressed in 40%-80% of late-stage metastatic cancers in the absence of gene amplification. Hdm2 regulates p53 stability via ubiquitination and has also been implicated in altering the sensitivity of cells to TGF-β1. Whether TGF-β1 signaling induces Hdm2 expression leading to HDM2-mediated destabilization of p53 has not been investigated. In this study, we report that TGF-β1-activated SMA- and MAD3 (Smad3/4) transcription factors specifically bound to the second promoter region of HDM2, leading to increased HDM2 protein expression and destabilization of p53 in human cancer cell lines. Additionally, TGF-β1 expression led to Smad3 activation and murine double minute 2 (Mdm2) expression in murine mammary epithelial cells during epithelial-to-mesenchymal transition (EMT). Furthermore, histological analyses of human breast cancer samples demonstrated that approximately 65% of late-stage carcinomas were positive for activated Smad3 and HDM2, indicating a strong correlation between TGF-β1-mediated induction of HDM2 and late-stage tumor progression. Identification of Hdm2 as a downstream target of TGF-β1 represents a critical prosurvival mechanism in cancer progression and provides another point for therapeutic intervention in late-stage cancer.

Original languageEnglish (US)
Pages (from-to)290-302
Number of pages13
JournalJournal of Clinical Investigation
Volume120
Issue number1
DOIs
StatePublished - Jan 4 2010

ASJC Scopus subject areas

  • Medicine(all)

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    Araki, S., Eitel, J. A., Batuello, C. N., Bijangi-Vishehsaraei, K., Xie, X. J., Danielpour, D., Pollok, K. E., Boothman, D. A., & Mayo, L. D. (2010). TGF-β1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer. Journal of Clinical Investigation, 120(1), 290-302. https://doi.org/10.1172/JCI39194