Although clinically associated with severe developmental defects, the biological function of FOXK2 remains poorly explored. Here we report that FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1β and EZH2 and to regulate several signaling pathways including the hypoxic response. We show that FOXK2 inhibits the proliferation and invasion of breast cancer cells and suppresses the growth and metastasis of breast cancer. Interestingly, FOXK2 is transactivated by ERα and transrepressed via reciprocal successive feedback by HIF1β/EZH2. Significantly, the expression of FOXK2 is progressively lost during breast cancer progression, and low FOXK2 expression is strongly correlated with higher histologic grades, positive lymph nodes, and ERα−/PR−/HER2- status, all indicators of poor prognosis. Display omitted •FOXK2 is a transcription repressor•FOXK2 is physically associated with multiple corepressor complexes•FOXK2 and its associated corepressor complexes target the hypoxia pathway•FOXK2 suppresses the growth and metastasis of breast cancer Shan et al. show that FOXK2 interacts with multiple corepressor complexes to repress the expression of a cohort of genes including HIF1β and EZH2. They show that an ERα-FOXK2-HIF1β/EZH2 axis is critically involved in breast cancer progression and that low FOXK2 expression correlates with poor prognosis.