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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTAs) are frontline chemotherapies for TNBC; however, the molecular pathways that cause TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening. We discovered that PTPN12 inactivation drives mitotic defects through aberrant hyperactivation of the ubiquitin ligase complex APCFZR1, a critical regulator of the cell cycle. Consistent with the mitotic stress caused by PTPN12 inactivation in TNBC cell lines, tumors harboring loss of PTPN12 exhibit heightened sensitivity to taxane chemotherapy. Collectively, this data suggests that PTPN12 inactivation may drive chromosomal instability and favorable MTA response in TNBC; two prominent features of the disease with unclear mechanistic etiology.