1. Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China
2. Department of General Surgery, the First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China
3. Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110003, China
* These authors contributed equally to this work.
Estrogen receptor α (ERα) is a key transcriptional factor in the proliferation and differentiation in mammary epithelia and has been determined to be an important predictor of breast cancer prognosis and therapeutic target. Meanwhile, diverse transcriptional co-regulators of ERα play crucial and complicated roles in breast cancer progression. Mediator of DNA damage checkpoint 1 (MDC1) has been identified as a critical upstream mediator in the cellular response to DNA damage, however, some non-DNA damage responsive functions of MDC1 haven't been fully defined. In this study, we have identified MDC1 as a co-activator of ERα in breast cancer cells and demonstrated that MDC1 associates with ERα. MDC1 was also recruited to estrogen response element (ERE) of ERα target gene. Knockdown of MDC1 reduced the transcription of the endogenous ERα target genes, including p21. MDC1 depletion led to the promotion of breast cancer progression, and the expression of MDC1 is lower in breast cancer. Taken together, these results suggested that MDC1 was involved in the enhancement of ERα-mediated transactivation in breast cancer cells. This positive regulation by MDC1 might contribute to the suppression of breast cancer progression by acting as a barrier of positive to negative ERα function transformation.
Keywords: estrogen receptor α, MDC1, co-activator, breast cancer, tumor suppression