Hormonal therapy is a rapidly progressing molecular-targeted therapy for breast cancer, using drugs such as LH-RH agonists, SERMs and aromatase inhibitors. Basic research for estrogen signaling and hormone sensitivity in breast cancer cells strongly contributes to the progression of clinical treatment of breast cancer. However, further problems remain unresolved, for example the accurate prediction of individual response to each hormonal therapy. Moreover, novel combinations with other molecular-targeted therapies might be advance the effectiveness of hormonal therapies. To address these issues, we are developing several new tools such as focused microarray and a GFP-reporter cell system. We first identified estrogen-responsive genes by comprehensive expression profiling of estrogen receptor (ER)-positive breast cancer cells, and produced a custom-made estrogen-responsive microarray of a narrowed-down subset. Using this microarray, we studied several basic issues regarding estrogen signaling and expression analysis of estrogen-responsive genes in breast cancer tissues. Furthermore, expression of several candidate genes selected from the contents of the customarray was also analyzed by real-time RT-PCR and by immunohistochemical techniques, to find new predictive factors for responsiveness to hormone therapy for primary breast cancer patients. We found that the expression of several genes such as HDAC6 significantly correlated with disease-free and overall survival of ER-positive patients. Furthermore, we are developing a new tool for analyzing the estrogen-related microenvironment on individual breast cancer patients using ERE-GFP-indicator cells. This system enables visualization of tumor-stroma interactions and the effects of aromatase inhibitors in an individual breast cancer sample. We believe that these approaches could provide not only new clues to elucidate the estrogen-dependent mechanisms of cancer, but also clinical benefits to patients by predicting individual response to hormonal therapy.
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