Abstract 4112: OTULIN promotes Wnt/β-Catenin activation by genotoxic treatments and enhances drug-resistance in breast cancer

Patients with basal-like breast cancer and triple-negative breast cancer (TNBC) generally have a worse prognosis than other breast cancer subtypes due to rapid-arising therapeutic resistance accompanied by aggressive metastasis. The drug-resistant tumor cells, including cancer stem-like cells with intrinsic resistance or tumor cells acquired resistance during treatments, could adopt a drug-tolerant state and serve as seeds for recurrent metastatic lesions. However, the molecular events orchestrating the innate and adaptive therapeutic resistance are not completely understood. We found that a linear ubiquitin-specific deubiquitinase OTULIN is overexpressed in breast tumors, especially in the basal-like subtype. Increased OTULIN levels were also observed in PDX samples from chemo-refractory TNBC patients compared to those were responsive to chemotherapy. OTULIN overexpression significantly increased TNBC cell resistance to chemotherapy and is associated with shorter OS and DFS in breast cancer patients. Mechanistically, we found genotoxic treatments induce OTULIN phosphorylation, which is required for the activation of Wnt/β-Catenin signaling in TNBC cells. Inhibiting Wnt/β-Catenin signaling or OTULIN sensitized TNBC xenografts to Doxorubicin treatment in vivo. In TNBC patients, increased OTULIN levels are higher in subtypes enriched with Wnt/β-catenin signaling signature. Our findings suggest that OTULIN may increase TNBC therapeutic resistance and aggressiveness by promoting Wnt/β-Catenin activation in response to chemotherapy. Targeting OTULIN and the chemotherapy-induced Wnt/β-Catenin activation may serve as a promising strategy to mitigate drug resistance and reduce metastasis in TNBC patients. Citation Format: Wei Wang, Li Mingqi, Yayun Chi, Jingyan Xue, Beshoy Fahmy, Jiong Wu, Zhaohui Wu. OTULIN promotes Wnt/β-Catenin activation by genotoxic treatments and enhances drug-resistance in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4112.