Abstract Chemotherapy is applied in over 70% of breast cancer patients. Antimicrotubule drugs and DNA-damaging drugs are the most popular medicine used for chemotherapy. However, it still lack of predictor for indicating which chemotherapy drug will benefit to patients. An urgent need is to develop biomarker used to determine which chemotherapy will work for individual patient. Antimicrotubule drugs such as docetaxel and vinorelbine are prescribed widely for breast cancer, nevertheless, about one-third of breast cancer patients suffer from the side effects of anti-microtubule drugs chemotherapy without benefit from it. Here, we report that PARK2 is a potential biomarker for chemosensitivity to antimicrotubule drugs in breast cancer. PARK2 gene encodes an E3 ubiquitin ligase. 34% of breast cancer patients exhibited PARK2 deletion. Interestingly, high PARK2 expression was positively correlated with favorable survival in breast cancer patients receiving chemotherapy, but not in those not receiving chemotherapy. Moreover, PARK2 overexpression specifically rendered cells more sensitive to antimicrotubule drugs, but not to DNA-damaging drugs. Depletion of PARK2 augmented resistance to antimicrotubule drugs. Mechanistically, PARK2 markedly activated the mitochondrial pathway of apoptosis after exposure to antimicrotubule drugs. This occurred through downregulating the antiapoptotic protein BCL-2. Notably, PARK2 physically interacted with BCL-2 and promoted ubiquitination of BCL-2 in an E3 ligase-dependent manner. Hence, PARK2 significantly enhanced the chemosensitivity of antimicrotubule drugs both in vitro and in vivo, while loss-of-function PARK2 mutants failed to enhance the sensitivity of antimicrotubule drugs. Taken together, we identified PARK2 as a novel mediator of antimicrotubule drug which provides a predictor for the chemosensitivity of antimicrotubule drugs in breast cancer. Citation Format: Hengxing Chen, Yun Li, Yu Li, Zhen Chen, Limin Xie, Wenjia Li, Yuanxin Zhu, Daning Lu, Xue Hong, H. Phillip Koeffler, Wenjing Wu, Kaishun Hu, Dong Yin. PARK2 enhances chemosensitivity of antimicrotubule drugs in breast cancer via promoting degradation of BCL-2 [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 72.