The histone demethylase JMJD2B is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth.

Estrogen receptor alpha (ERalpha) plays an important role in breast cancer. Upregulation of HIF-1alpha in ER(alpha)-positive cancers suggests that HIF-1alpha may cooperate with ERalpha to promote breast cancer progression and consequently affect breast cancer treatment. Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. We also show that JMJD2B and the hypoxia marker CA9 together stratify a subclass of breast cancer patients and predict a worse outcome of these breast cancers. Our findings provide a biological rationale to support the therapeutic targeting of histone demethylases in breast cancer patients.