Estrogen and growth factor signaling pathway: basic approaches for clinical application

Estrogen and its receptor play important roles in genesis and malignant progression of estrogen-dependent cancers, together with various growth factors. Functional cross-talk between estrogen-signaling and growth factor-mediated signaling pathways has been reported. Firstly, we show an example of the cross-talk that may alter the effect of antagonist on the breast and endometrial cancer cell growth. Our observations suggest that the constitutively activated MAP kinase-signaling pathway in endometrial cancer cells might enhance the transcriptional activity of ERalpha via phosphorylation of AF-1 domain. This mechanism may cause the growth stimulative effect of tamoxifen on the endometrium. Secondly, we show our recent study for comprehensive understanding of estrogen-signaling pathway using cDNA microarray. According to the results of the expression profiling of estrogen-responsive genes in ER-positive breast cancer cells using large-scale cDNA microarray, the custom-made cDNA microarray, on which only estrogen-responsive genes were loaded, was produced. Using this microarray consisting of the narrowed gene subset, we analyzed estrogen responsiveness of various cell lines and effect of estrogen antagonists. Aim of this study is not only to address the molecular mechanisms of estrogen-dependent growth of breast cancer, but also to develop the new diagnostic tools for responsiveness to hormone therapy of primary breast cancer patients. Finally, in order to understand the local tumor biology including stroma-cancer interaction, we recently developed the new analytical system using ERE-GFP introduced into breast cancer cells. Several observations indicated that these reporter cells were useful for assessment of stimulative effects of stroma cells adjacent to breast cancer on the estrogen-signaling pathway. These studies may provide not only new clues for elucidation of the molecular mechanisms of estrogen-dependent growth of breast cancer, but also assessment of anti-estrogen responses of individual breast cancer for patient-tailored hormone therapy.