Estrogen signaling in cancer microenvironment and prediction of response to hormonal therapy

Estrogen plays an essential role in growth and progression of human breast cancer. Particularly, local estrogen biosynthesis must be important for etiology of this disease. Since estrogen signaling is also activated by the growth factor-mediating phosphorylation signal, breast cancer strongly depends upon local cancer microenvironment. Then, to analyze the estrogen-related cancer microenvironment of individual breast cancer tissues, we established new reporter cell system, which was stably transfected GFP reporter DNA inserted estrogen response element in MCF-7 cells. It enables to analyze ERalpha-activation activity of stromal cells in individual cancer patients. We found that ERalpha-activation activity and effect of aromatase inhibitors varied among the individual cases but correlated with histological grade, indicating that the ability of stromal cells in adjacent to cancer cells must be unique and important. Furthermore, these ERalpha-activation signals in the microenvironment stimulate following intracellular estrogen-signal transduction in cancer cells. Our estrogen-responsive microarray analysis, real-time RT-PCR, and immunohistochemical technique revealed several new target genes which correlate with prognosis of breast cancer and play an important role in cancer development. For example, we found that transcription factor EGR3 was the bona fide target gene for ERalpha and might involve with invasive property in breast cancer. Furthermore, the expression of another downstream gene HDAC6 significantly correlated with survival of breast cancer patients. In vitro study revealed that the HDAC6 caused the deacetylation of alpha-tubulin in cytosol and induced cell motility in ERalpha-positive breast cancer cells. We hope that these approaches could provide not only new clues for elucidation of the mechanisms of estrogen-dependent growth and development of breast cancer, but also clinical benefits to patients by assessment of individual response to hormonal therapy.