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

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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.