ZEB1 Upregulates MSRB3 to Suppress Oncogene-Induced DNA Damage

Chromosomal instability (CIN) drives tumorigenesis in many adult neoplasms. However, some tumor types, including a subset of triple-negative breast cancers (TNBC), harbor few genomic alterations, suggesting that in these tumors oncogenic transformation occurs independently of CIN. Claudin-low TNBCs exhibit low CIN and may originate from early epithelial precursor cells with stem cell features, prompting Morel and colleagues to hypothesize that traits of the cell of origin might influence genomic instability. A hierarchy of normal human mammary epithelial cells was established and their differentiation potential was evaluated. Three mammary stem cell–enriched populations were identified. These cells were resistant to oncogene-induced DNA damage, whereas RAS activation or Cyclin E overexpression induced massive DNA damage in more differentiated cell types. Gene expression analysis showed that mammary stem cells and TNBCs with low CIN had increased expression of epithelial–mesenchymal transition–inducing transcription factors including ZEB1. ZEB1 suppressed oncogene-induced DNA damage by reducing reactive oxygen species (ROS). Mechanistically, ZEB1 bound to the promoter of the antioxidant methionine sulfoxide reductase gene MSRB3, promoting MSRB3 expression to suppress ROS production after oncogene activation. Accordingly, MSRB3 was highly expressed in mammary stem cells compared with more differentiated cells, and MSRB3 expression was inversely correlated with CIN in breast cancer cell lines and primary TNBCs. Analysis of data from The Cancer Genome Atlas showed that low expression of ZEB1 predicts CIN and TP53 mutations across various tumor types. Further, ZEB1-mediated suppression of CIN may prevent induction of the p53-dependent DNA-damage response to promote transformation. Altogether, these findings suggest that ZEB1 expression prevents oncogene-induced DNA damage and CIN in stem cells, and indicate that the cellular differentiation state may determine the genetic route to oncogenic transformation.

Morel AP, Ginestier C, Pommier RM, Cabaud O, Ruiz E, Wicinski J, et al. A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability. Nat Med 2017;23:568–78.

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