Yamaguchi Yuri
Research Institute for Clinical Oncology, Saitama Cancer Center, Japan.
Breast Cancer. 2007;14(2):175-81. doi: 10.2325/jbcs.975.
In breast cancers, estrogen activates estrogen receptor (ER) through genomic and nongenomic pathways, which leads to nuclear and extranuclear processes that promote the proliferation of breast cancer cells. Growth factor receptor signaling pathways also activate ER via phosphorylation through the signal crosstalks between estrogen and growth factors. The intratumoral levels of estrogen and growth factors, therefore, profoundly influence ER activity, which are regulated by the tumor-stromal interactions in the microenvironment. 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 endocrine therapy for breast cancers. We developed a comprehensive system to evaluate the ER-activating ability of stromal fibroblasts for individual patients, and found that it varied among individual cases. This system might be useful for predicting the individual response to endocrine therapy and analyzing the tumor microenvironment. In addition to estrogen production, tumor-associated fibroblasts lead to the progression of breast cancer via different pathways. A study to differentiate the microenvironmental regulation of estrogen-dependent and -independent breast cancer growth would also be useful to improve hormone therapy for breast cancer.
在乳腺癌中，雌激素通过基因组和非基因组途径激活雌激素受体（ER），这会引发促进乳腺癌细胞增殖的核内和核外过程。生长因子受体信号通路也通过雌激素与生长因子之间的信号串扰，经由磷酸化作用激活ER。因此，肿瘤内雌激素和生长因子的水平会深刻影响ER活性，而这又受到微环境中肿瘤-基质相互作用的调控。在绝经后乳腺癌中，肿瘤细胞激活基质成纤维细胞以表达芳香化酶，这是雌激素生物合成中的一种关键酶，从而导致肿瘤内雌激素的产生。目前，芳香化酶抑制剂被用作乳腺癌的一线内分泌治疗药物。我们开发了一个综合系统来评估个体患者基质成纤维细胞的ER激活能力，发现其在不同个体病例中存在差异。该系统可能有助于预测个体对内分泌治疗的反应并分析肿瘤微环境。除了雌激素的产生，肿瘤相关成纤维细胞还通过不同途径导致乳腺癌的进展。一项区分雌激素依赖性和非依赖性乳腺癌生长的微环境调控的研究，对于改善乳腺癌的激素治疗也将是有益的。
