Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan.
Biochem Biophys Res Commun. 2010 Feb 12;392(3):357-62. doi: 10.1016/j.bbrc.2010.01.025. Epub 2010 Jan 13.
It has been well established that estrogen is involved in the pathophysiology of breast cancer. Estrogen receptor (ER) alpha appears to promote the proliferation of cancer tissues, while ERbeta can protect against the mitogenic effect of estrogen in breast tissue. The expression status of ERalpha and ERbeta may greatly influence on the development, treatment, and prognosis of breast cancer. Previous studies have indicated that the deleted in breast cancer 1 (DBC1/KIAA1967) gene product has roles in regulating functions of nuclear receptors. The gene encoding DBC1 is a candidate for tumor suppressor identified by genetic search for breast cancer. Caspase-dependent processing of DBC1 promotes apoptosis, and depletion of the endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. In addition, DBC1 modulates ERalpha expression and promotes breast cancer cell survival by binding to ERalpha. Here we report an ERbeta-specific repressive function of DBC1. Immunoprecipitation and immunofluorescence studies show that ERbeta and DBC1 interact in a ligand-independent manner similar to ERalpha. In vitro pull-down assays revealed a direct interaction between DBC1 amino-terminus and activation function-1/2 domain of ERbeta. Although DBC1 shows no influence on the ligand-dependent transcriptional activation function of ERalpha, the expression of DBC1 negatively regulates the ligand-dependent transcriptional activation function of ERbetain vivo, and RNA interference-mediated depletion of DBC1 stimulates the transactivation function of ERbeta. These results implicate the principal role of DBC1 in regulating ERbeta-dependent gene expressions.
已经证实雌激素参与乳腺癌的病理生理学。雌激素受体（ER）α似乎促进癌组织的增殖，而 ERβ可以保护乳腺组织免受雌激素的促有丝分裂作用。ERα和 ERβ的表达状态可能对乳腺癌的发展、治疗和预后产生重大影响。先前的研究表明，乳腺癌缺失基因 1（DBC1/KIAA1967）的产物在调节核受体功能方面具有作用。编码 DBC1 的基因是通过遗传搜索鉴定的乳腺癌候选肿瘤抑制基因。DBC1 的 caspase 依赖性加工促进细胞凋亡，并且通过其对 SIRT1 的特异性抑制，内源性 DBC1 的耗竭负调节 p53 依赖性细胞凋亡。此外，DBC1 通过与 ERα结合来调节 ERα的表达并促进乳腺癌细胞存活。在这里，我们报告了 DBC1 的一种 ERβ特异性抑制功能。免疫沉淀和免疫荧光研究表明，ERβ和 DBC1以类似于 ERα的方式以配体非依赖性方式相互作用。体外下拉测定显示 DBC1 的氨基末端与 ERβ的激活功能-1/2 结构域之间存在直接相互作用。尽管 DBC1 对 ERα的配体依赖性转录激活功能没有影响，但 DBC1 的表达负调节 ERβ的配体依赖性转录激活功能，并且 RNA 干扰介导的 DBC1 耗竭刺激 ERβ的转录激活功能。这些结果表明 DBC1 在调节 ERβ依赖性基因表达中起主要作用。
