MDC1 Enhances Estrogen Receptor-mediated Transactivation and Contributes to Breast Cancer Suppression

Abstract

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.

Polymorphisms in homologous recombination repair genes and the risk and survival of breast cancer

“…Previous evidence indicates that MDC1 was a tumor suppressor gene in the development of BC . MDC1 has also been identified as a co‐activator of ERα in BC cells and its depletion led to the promotion of BC progression, which was consistent to some extent with one of the present results showing that the association between the variant alleles of NRM rs1075496 and a poorer PFS of BC occurred among only patients who were ER positive but not those who were ER negative, although the interaction was not significant (data not shown). In addition, our results suggest that the variant alleles of LIG3 rs1052536 were significantly associated with a better prognosis of BC, which was consistent to some extent with the result of a previous study reporting that patients with the variant genotypes of LIG3 rs476030 (linkage to rs1052536) had a significantly better disease‐free survival in squamous cell carcinomas of the non‐oropharynx, whereas another previous study showed no relationship between variant genotype of LIG3 and BC risk .…”

DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis

“…Indeed, MDC1 role in tumor progression is still contradictory: it has been associated with more aggressive phenotypes of cervical and ovarian cancer, 21,22 but it has been reported to be downregulated in breast tumor in comparison with benign hyperplasia. 23 An important finding of this study is the correlation observed between PAXIP1 and TP53BP1 expression ( Fig. 1B and C), and their downregulation association with worse prognosis ( Table 2, Fig.…”

Linking DNA Damage and Hormone Signaling Pathways in Cancer

“…Studies have implicated MDC1 in regulating ER, wherein MDC1 directly binds to and increases the transactivation potential of ER, and also resides at sites of ER activity on chromatin. Interestingly, MDC1 levels decrease as a function of BrCa progression, and knockdown of MDC1 results in increased tumorigenic phenotypes, suggesting that the MDC1-dependent ER transcriptional program actually blocks cancer progression [61, 62]. Based on the studies outlined above, part of the functional output of the DDR machinery is to positively regulate ER function (table 1).…”