Microenvironmental regulation of estrogen signals in breast cancer

雌激素在人类乳腺癌的生长和进展中起着重要作用。在绝经后乳腺癌中，肿瘤细胞激活基质成纤维细胞表达芳香化酶，这是雌激素生物合成的关键酶，导致肿瘤内雌激素产生。目前，芳香化酶抑制剂被用作乳腺癌内分泌治疗的一线治疗。雌激素信号传导也通过生长因子介导的雌激素受体磷酸化激活，这强烈依赖于局部癌症微环境。然后，为了分析个体乳腺癌组织中雌激素相关的癌症微环境，我们建立了一种新的报告细胞系统，通过转染GFP报告DNA插入雌激素反应元件到MCF-7细胞中。它使我们能够分析单个癌症患者的基质细胞的ER α激活活性。使用系统，我们发现，在每种情况下，基质成纤维细胞有自己的属性方面的激活雌激素信号。芳香化酶抑制剂能有效抑制间质成纤维细胞诱导的ER激活，但对药物的敏感性各不相同。雌激素途径也起着重要作用。在人子宫内膜癌的发生发展中的作用，并利用ERE-GFP报告系统，我们获得了类似的结果。为了更容易地评估GFP表达，我们开发了GFP表达的自动图像分析系统。虽然需要进一步的详细研究，ERE-GFP检测系统可能是一个有用的工具，用于分析雌激素相关的微环境在个别乳腺癌和肿瘤间质相互作用的机制，在肿瘤进展。此外，我们确定了乳腺癌组织的上清液中的乳腺癌细胞的生长刺激活性，这是不被抑制的抗雌激素药物，但部分抑制抗HGF抗体。

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.