Microenvironmental regulation of estrogen signals in breast cancer.

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.