Bidany-Mizrahi Tirza, Shweiki Aya, Maroun Kian, Abu-Tair Lina, Mali Bella, Aqeilan Rami I
The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Pathology, Hadassah University Hospital, Jerusalem, Israel.
Cell Death Discov. 2024 Mar 18;10(1):145. doi: 10.1038/s41420-024-01878-8.
Breast cancer is the leading cause of cancer-related deaths in women worldwide, with the basal-like or triple-negative breast cancer (TNBC) subtype being particularly aggressive and challenging to treat. Understanding the molecular mechanisms driving the development and progression of TNBC is essential. We previously showed that WW domain-containing oxidoreductase (WWOX) is commonly inactivated in TNBC and is implicated in the DNA damage response (DDR) through ATM and ATR activation. In this study, we investigated the interplay between WWOX and BRCA1, both frequently inactivated in TNBC, on mammary tumor development and on DNA double-strand break (DSB) repair choice. We generated and characterized a transgenic mouse model (K14-Cre;Brca1;Wwox) and observed that mice lacking both WWOX and BRCA1 developed basal-like mammary tumors and exhibited a decrease in 53BP1 foci and an increase in RAD51 foci, suggesting impaired DSB repair. We examined human TNBC cell lines harboring wild-type and mutant BRCA1 and found that WWOX expression promoted NHEJ repair in cells with wild-type BRCA1. Our findings suggest that WWOX and BRCA1 play an important role in DSB repair pathway choice in mammary epithelial cells, underscoring their functional interaction and significance in breast carcinogenesis.
乳腺癌是全球女性癌症相关死亡的主要原因，其中基底样或三阴性乳腺癌（TNBC）亚型尤其具有侵袭性且治疗具有挑战性。了解驱动TNBC发生和发展的分子机制至关重要。我们之前表明，含WW结构域氧化还原酶（WWOX）在TNBC中通常失活，并通过ATM和ATR激活参与DNA损伤反应（DDR）。在本研究中，我们研究了在TNBC中经常失活的WWOX和BRCA1之间在乳腺肿瘤发生以及DNA双链断裂（DSB）修复选择上的相互作用。我们构建并表征了一种转基因小鼠模型（K14-Cre;Brca1;Wwox），观察到同时缺乏WWOX和BRCA1的小鼠发生了基底样乳腺肿瘤，并且53BP1病灶减少而RAD51病灶增加，提示DSB修复受损。我们检测了携带野生型和突变型BRCA1的人TNBC细胞系，发现WWOX表达促进了具有野生型BRCA1的细胞中的非同源末端连接（NHEJ）修复。我们的研究结果表明，WWOX和BRCA1在乳腺上皮细胞的DSB修复途径选择中起重要作用，强调了它们在乳腺癌发生中的功能相互作用和意义。
