USP11 deubiquitinates E-cadherin and maintains luminal fate of mammary cells to suppress breast cancer

Abstract Background: Basal-like breast cancer may originate from luminal epithelial or cancerous cells. Inadequately repaired DNA damage impairs luminal differentiation and promotes aberrant luminal to basal trans-differentiation in mammary epithelial cells. USP11, a deubiquitinase, plays a critical role in DNA damage repair. The role of USP11 in controlling mammary cell differentiation and tumorigenesis remains poorly understood. Methods: We generated Usp11 knock-out mice and breast cancer cell lines expressing wild type and mutant form of USP11. By using these mutant mice, cell lines, and human USP11 deficient and proficient breast cancer tissues, we tested how USP11 controls mammary cell fate. Results: We generated Usp11 knock-out mice and found that deletion of Usp11 impaired luminal differentiation and promoted DNA damage in mammary epithelial cells. Over-expression of wild-type (WT) USP11, not a deubiquitinase-inactive mutant form of USP11, promoted luminal and epithelial differentiation, enhanced DNA damage repair, and suppressed tumorigenesis in mice. Mechanistically, we found that Usp11 enhanced the protein expression of E-cadherin dependent on its deubiquitinase activity. We discovered that USP11 bound to E-cadherin through its C-terminal region, and that USP11 was a deubiquitinase of E-cadherin. In human breast cancers, expression of USP11 was positively correlated with that of E-cadherin and high USP11 predicted a better recurrence-free survival. Conclusions: Our findings provide compelling genetic and biochemical evidence that USP11 not only promotes DNA damage repair, but also deubiquitinates E-cadherin and maintains the luminal feature of mammary epithelial and cancerous cells, to suppress breast cancer.