Oncogenic features of the JMJD2A histone demethylase in breast cancer

Estrogen receptor alpha (ER alpha) plays a pivotal role in the genesis of the majority of breast tumors. Consequently, endocrine therapy is now routinely utilized in the clinic for the treatment of ER alpha-positive breast cancer patients. However, how ER alpha activity becomes dysregulated in breast cancer cells remains to be elucidated. The aim of this study was to show that the histone demethylase JMJD2A, also known as KDM4A, is capable of forming a complex with ER alpha in vivo. Moreover, wild-type JMJD2A, but not a catalytically impaired mutant, was able to strongly coactivate ER alpha-mediated transcription. Consistently, the downregulation of JMJD2A in human T47D breast cancer cells led to a decreased expression of cyclin D1, a prominent ER alpha target gene and cell cycle regulator. The downregulation of JMJD2A induced a reduction in the growth of T47D cells. In addition, we found that JMJD2A is overexpressed in human breast tumors both at the mRNA and protein level. Taken together, these data indicate that the overexpression of JMJD2A may contribute to breast tumor formation by stimulating ER alpha activity and that JMJD2A may be a breast-relevant oncoprotein. As such, small molecule drugs targeting the catalytic center of JMJD2A might be useful in breast cancer adjuvant therapy.