We previously identified KDM5B, encoding a histone H3 lysine 4 (H3K4) demethylase, as an oncogene in estrogen receptor positive (ER+) breast cancer driving endocrine resistance. Here we describe that KDM5A is frequently amplified and overexpressed in basal breast tumors and is associated with chemotherapy resistance. Using CRISPR knockout viability screens -/+ KDM5 inhibition (KDM5i), we found that deletion of the transcription factor ZBTB7A and core SAGA complex increased sensitivity to KDM5i, whereas knockout of RHO-GTPases led to resistance. Integrated ChIP-seq and RNA-seq analyses revealed colocalization of ZBTB7A and KDM5s at promoters with high H3K4me3 signal and dependence of KDM5A binding on ZBTB7A. ZBTB7A knockout had a pleiotropic effect on transcriptional responses to KDM5i, in which it modulates the KDM5i-induced innate immune signaling and NF-kB-regulated genes. ZBTB7A knockout and KDM5i cooperate to alter cell states with KDM5i decreasing basal-like and ZBTB7A knockout inducing mesenchymal-like gene expression patterns. Our work furthers our understanding of KDM5-mediated gene regulation in breast cancer and identifies key pathways that mediate sensitivity to KDM5 inhibition Overall design: To investigate resistance to the KDM5 inhibitor C70, we generated a C70-resistant cell line through prolonged passaging in 10 µM C70 (i.e., SUM149CR). The SUM149CR derivative and parental SUM149 cells were treated for 2 or 7 days -/+ 10 µM C70 and compared via RNA-seq. Since our CRISPR screen identified ZBTB7A as a modulator of C70-sensitivity, we aimed to test the effect of ZBTB7A knockout on transcriptional response to C70. We developed ZBTB7A knockouts across multiple cell lines: SUM149, MDA-MB-436, MCF7, and T-47D. As a WT control, cells expressing the ROSA26-targeting gRNA (i.e., ROSA26-KOs) were generated. All cell lines were treated for 7 days -/+ 10 µM C70 and the effect of ZBTB7A-KO on transcriptional response was assessed.