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.