Expression and functional modulation of estrogen receptor α in human breast cancer

我们已经研究了人类乳腺癌发生的分子机制，从雌激素受体（ER）的癌症特异性调节的角度，如ERα基因表达和ER功能的改变。ERα的表达在乳腺癌的发生过程中急剧增加，然后随着癌症的发展而下降。首先，我们评估了在乳腺癌中调节ERα基因表达的分子机制，确定了一个重要的顺式元件，该元件在乳腺癌中主要使用。具体来说，通过鉴定一种新的转录因子（ERBF-1）和启动子的甲基化，证明了反式和顺式作用因子的作用。阐明ERα基因的表达机制，对于开发针对ERα基因特异性启动子的乳腺癌早期检测和化学预防的新工具具有重要意义。此外，我们还评估了癌症相关基因产物p53和MDM2对ERα的癌症特异性功能调节。野生型p53降低ERα的功能；MDM2通过依赖和独立于p53的两条途径增强功能。这一发现为临床观察到的MDM2在er阳性乳腺癌中的过表达提供了合理的解释。MDM2似乎可以抑制p53诱导的内质网功能衰减引起的生长抑制。我们认为这些结果有助于基于机制的乳腺癌靶向治疗的未来发展。

We have been investigated the molecular mechanisms of human breast carcinogenesis, in terms of the cancer-specific modulation of estrogen receptor (ER), such as altered regulation of ERα gene expression and ER function.Expression of ERα dramatically increases in the genesis of breast cancer, and then it decreases with cancer development. First we assessed the molecular mechanisms of regulating ERα gene expression in breast cancer, identifying an important cis-element, which is predominantly utilized in breast cancer. Specifically, the role of trans- and cis-acting factors was demonstrated by identification of a novel transcription factor (ERBF-1) and methylation of the promoters. Elucidation of mechanism of ERα gene expression is important to develop a new tool for early detection of breast cancer along with the chemoprevention targeting specific promoters of ERα gene.Furthermore, we also assessed the cancer-specific functional modulation of ERα by cancer-related gene products, p53 and MDM2. The wild-type p53 diminished the function of ERα ; MDM2 enhanced the function through the two pathways dependent and independent of p53. This finding provides a reasonable interpretation to the clinically observed overexpression of MDM2 in ER-positive breast cancer. MDM2 seems to squelch the growth suppression caused by p53-induced attenuation of ER function. These results we thought to help the future development of mechanism-base target-oriented therapy of breast cancer.