A functional role for an intronic enhancer of the ZBTB16 gene in AR-mediated tumour suppression in ER+ breast cancer

We previously identified ZBTB16 as a candidate AR-regulated tumour suppressor gene. Here, we validated ZBTB16 as a direct AR target and tested whether it mediates AR tumour suppressor activity.

In clinical cohorts, ZBTB16 mRNA expression was reduced in breast tumours relative to normal tissue, and higher expression correlated with improved survival in ER+ disease. Androgen treatment increased ZBTB16 protein in ER+ breast cancer cell lines, but ZBTB16 knockdown or overexpression did not detectably alter AR anti-proliferative effects in the models tested. AR bound a conserved intron 3 hormone response region (HRRINT3) within the ZBTB16 locus in breast cancer models and clinical specimens, with androgen-dependent H3K27ac enrichment, consistent with an AR-responsive enhancer.