Gene expression analysis of breast cancers has discerned three molecular subtypes—luminal, basal, and mesenchymal—across the classically defined (ER+, HER2+ and triple-negative, or TNBC) types of the cancer. Ludwig Harvard’s Kornelia Polyak and her colleagues have previously identified epigenetic enzyme KDM5B, a histone demethylase, as a luminal lineage-driving oncogene frequently amplified in ER+ breast tumors that also contributes to endocrine therapy resistance. That oncogene’s paralog, KDM5A, appears to play a similar and redundant role in ER+ tumors. In a December issue of Cell Reports, Kornelia and her team described their findings from a follow-up study exploring KDM5A’s role in basal and triple-negative breast cancers. They reported that KDM5A is specifically amplified and overexpressed in basal breast tumors and its inhibition suppresses the growth of a KDM5A-amplified basal TNBC cell line. The researchers used this cell line to perform CRISPR screens to identify proteins that modulate sensitivity to the inhibitor. They discovered that deletion of the ZBTB7A transcription factor and core SAGA complex—a multi-subunit, enzymatic coactivator of transcription—sensitizes cells to KDM5 inhibition, while deletion of RHO-GTPases confers resistance to the KDM5 inhibitor. The researchers showed that KDM5A binding depends on ZBTB7A and described the molecular mechanisms associated with this effect. They also reported that high ZBTB7A expression is associated with poor response to neoadjuvant chemotherapy in triple-negative breast cancer.
ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer
Cell Reports, 2024 December 24