Abstract
MTDH is indispensable for tumor-initiating cell function in multiple breast cancer subtypes.
Major finding: MTDH is indispensable for tumor-initiating cell function in multiple breast cancer subtypes.
Mechanism: Interaction of MTDH with SND1 promotes survival of mammary epithelial cells under stress.
Impact: Targeted inhibition of the MTDH–SND1 complex may reduce breast cancer initiation and progression.
Metadherin (MTDH) overexpression is associated with metastasis and poor prognosis in breast cancer. Recent studies have implicated MTDH in the regulation of proliferation, invasion, and angiogenesis, and have linked MTDH with oncogenic pathways; however, full understanding of the role of MTDH in tumorigenesis remains elusive. Utilizing gene-trapped Mtdh-knockout mice, Wan and colleagues found that MTDH was required for the formation of luminal, basal-like, and mixed subtypes of mammary tumors. Specifically, depletion of Mtdh diminished the expansion and tumorigenic potential of tumor-initiating cells (TIC) in preneoplastic mammary glands, but was largely dispensable for normal mammary stem cell function. Reintroduction of Mtdh in mammary epithelial cells (MEC) reestablished the tumorigenic potential of oncogene-induced TICs, demonstrating the requirement for MTDH in mammary tumor initiation. Mechanistically, expression of Staphylococcal nuclease domain-containing 1 (SND1) and its interaction with MTDH were necessary for MTDH-initiated tumor formation; MTDH-mediated stabilization of SND1 protein conferred a survival advantage in MECs and enhanced cell viability under stress via upregulation of prosurvival genes. In addition, mutational analysis revealed that the MTDH–SND1 interaction was requisite to promote the tumorigenic potential of TICs. In human breast cancer cell lines and xenografts, silencing of either MTDH or SND1 compromised sphere formation and impaired in vivo tumor formation. Expression of MTDH and SND1 were correlated in human breast cancer samples, corroborating the role of MTDH in regulating SND1 levels. Furthermore, analysis of patient data showed that high expression of MTDH and SND1 were correlated with larger, poorly differentiated tumors and shorter metastasis-free survival, and that elevated MTDH levels predicted poor prognosis in multiple breast cancer subtypes. In sum, these data implicate MTDH–SND1 in breast cancer initiation and metastasis and suggest that inhibition of this complex may limit breast cancer progression.