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MTDH-SND1 Interaction Is Crucial for Expansion and Activity of Tumor-Initiating Cells in Diverse Oncogene- and Carcinogen-Induced Mammary Tumors
Ist Teil von
Cancer cell, 2014-07, Vol.26 (1), p.92-105
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2014
Quelle
ScienceDirect
Beschreibungen/Notizen
The Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis; however, its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH supports the survival of mammary epithelial cells under oncogenic/stress conditions by interacting with and stabilizing Staphylococcal nuclease domain-containing 1 (SND1). Silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenenic potential of TICs in vivo. This functional significance of MTDH-SND1 interaction is further supported by clinical analysis of human breast cancer samples.
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•MTDH deficiency inhibits diverse oncogene- or carcinogen-induced tumorigenesis•MTDH is selectively required for TICs but not normal mammary stem cells•MTDH-mediated stabilization of SND1 confers survival advantage under stress•MTDH interaction is required for SND1-dependent expression of prosurvival genes
Wan et al. show that metadherin (MTDH) is important for mammary tumor-initiating cells (TIC), but not for mammary stem cells. MTDH interacts with SND1 to support mammary epithelial cell survival under oncogenic/stress conditions; interfering with this interaction reduces TIC tumorigenenic potential.