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

• Published in: The Journal of clinical investigation 2010-01, Vol.120 (1), p.290-302
• Main Authors: Araki, Shinako, Eitel, Jacob A, Batuello, Christopher N, Bijangi-Vishehsaraei, Khadijeh, Xie, Xian-Jin, Danielpour, David, Pollok, Karen E, Boothman, David A, Mayo, Lindsey D
• Format: Article
• Language: English
• Subjects: Breast cancer; Care and treatment; Development and progression; Gene expression; Metastasis; Physiological aspects; Properties; Transforming growth factors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI39194

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.