MDC1 Enhances Estrogen Receptor-mediated Transactivation and Contributes to Breast Cancer Suppression.
MDC1 Enhances Estrogen Receptor-mediated Transactivation and Contributes to Breast Cancer Suppression.
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MDC1 增强雌激素受体介导的反式激活并有助于抑制乳腺癌
DOI：
10.7150/ijbs.10918
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发表时间：
2015
影响因子：
9.2
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Zou R;Zhong X;Wang C;Sun H;Wang S;Lin L;Sun S;Tong C;Luo H;Gao P;Li Y;Zhou T;Li D;Cao L;Zhao Y
雌激素受体α（Estrogen receptor α，ERα）是乳腺上皮细胞增殖和分化的关键转录因子，是乳腺癌预后的重要预测因子和治疗靶点。同时，ERα的多种转录辅助调节因子在乳腺癌的发生、发展过程中起着重要而复杂的作用。DNA损伤检查点1（MDC1）是细胞对DNA损伤应答的重要上游介质，但其非DNA损伤应答功能尚不完全清楚。在这项研究中，我们已经确定了MDC1作为乳腺癌细胞中ERα的共激活因子，并证明MDC1与ERα相关。MDC1也被募集到ERα靶基因的雌激素反应元件（ERE）上。MDC1的敲除降低了内源性ERα靶基因（包括p21）的转录。MDC1缺失导致乳腺癌进展的促进，并且MDC1在乳腺癌中的表达较低。综上所述，这些结果表明，MDC1参与增强乳腺癌细胞中ERα介导的反式激活。MDC1的这种正性调节可能通过作为ERα功能正向负向转化的屏障而有助于抑制乳腺癌的进展。
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.