Microenvironmental regulation of estrogen signals in breast cancer

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Estrogen plays an essential role in growth and progression of human breast cancers. In postmenopausal breast cancers, tumor cells activate stromal fibroblasts to express aromatase, a key enzyme in estrogen biosynthesis, resulting in intratumoral estrogen production. At present, aromatase inhibitors are used as a first line treatment in endocrine therapy for breast cancers. Estrogen signaling is also activated by the growth factor-mediating phosphorylation of estrogen receptor, which strongly depends upon local cancer microenvironment. Then, to analyze the estrogen-related cancer microenvironment of individual breast cancer tissues, we established a new reporter cell system by transfection with GFP reporter DNA inserted estrogen response element into MCF-7 cells. It enables us to analyze ERa-activation activity of stromal cells for individual cancer patients. Using system, we found that stromal fibroblasts in each case have their own properties with respect to the activation of estrogen signals. Aromatase inhibitors effectively inhibited stromal fibroblasts-induced ER activation but the sensitivities to the drugs were different form each case. The estrogen pathway also plays an important role. in the development of human endometrial carcinoma, and using ERE-GFP reporter system, we obtained similar results. To more easily evaluate GFP expression, we developed an automated image analysis system of GFP expression. Although further detailed study is required, this ERE-GFP assay system might be a useful tool for analyzing the estrogen-related microenvironment in individual breast cancers and the mechanisms of tumor-stromal interactions in tumor progression. Furthermore, we identified growth-stimulating activity for breast cancer cells in the supernatant of breast cancer tissues, which was not inhibited by anti-estrogen drugs but partly inhibited by anti-HGF antibody.