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 (MECs). Ubiquitin-specific peptidase 11 (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. We generated Usp11 knockout mice and breast cancer cell lines expressing wild-type (WT) and mutant forms 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. We generated Usp11 knock-out mice and found that deletion of Usp11 reduced the expression of E-cadherin and promoted DNA damage in MECs. Overexpression of WT USP11, but not a deubiquitinase-inactive mutant form of USP11, promoted luminal 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 and that USP11 deubiquitinated E-cadherin at K738. We discovered that USP11 is bound to E-cadherin through its C-terminal region. In human breast cancers, expression of USP11 was positively correlated with that of E-cadherin, and high USP11 predicted better recurrence-free survival. 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 tumor cells, thereby suppressing luminal breast cancer.

中文翻译：

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USP11 使 E-钙粘蛋白去泛素化并维持乳腺肿瘤细胞的管腔命运以抑制乳腺癌


基底样乳腺癌可能起源于管腔上皮细胞或癌细胞。未充分修复的 DNA 损伤会损害管腔分化，并促进乳腺上皮细胞 （MEC） 中异常的管腔到基底反式分化。泛素特异性肽酶 11 （USP11） 是一种去泛素酶，在 DNA 损伤修复中起关键作用。USP11 在控制乳腺细胞分化和肿瘤发生中的作用仍然知之甚少。我们生成了表达 USP11 野生型 （WT） 和突变形式的 Usp11 敲除小鼠和乳腺癌细胞系。通过使用这些突变小鼠、细胞系和人类 USP11 缺陷和熟练的乳腺癌组织，我们测试了 USP11 如何控制乳腺细胞命运。我们生成了 Usp11 敲除小鼠，发现 Usp11 的缺失降低了 E-cadherin 的表达并促进了 MEC 中的 DNA 损伤。WT USP11 的过表达，而不是 USP11 的去泛素酶失活突变形式，促进小鼠管腔分化，增强 DNA 损伤修复，并抑制肿瘤发生。从机制上讲，我们发现 USP11 增强了 E-钙粘蛋白的蛋白表达，这取决于其脱泛素酶活性，并且 USP11 在 K738 位点使 E-钙粘蛋白脱泛素。我们发现 USP11 通过其 C 端区域与 E-钙粘蛋白结合。在人乳腺癌中，USP11 的表达与 E-cadherin 的表达呈正相关，高 USP11 预示着更好的无复发生存期。我们的研究结果提供了令人信服的遗传和生化证据，表明 USP11 不仅促进 DNA 损伤修复，而且使 E-钙粘蛋白去泛素化并维持乳腺肿瘤细胞的管腔特征，从而抑制管腔乳腺癌。