Cellular Imaging Technologies for Discovering Improved Breast Cancer Therapies

摘要

This idea award was approved to study SERM-selective interactions of estrogen receptors alpha and beta with interacting factors. In this first year, we developed highly integrated cellular imaging techniques that measured not only ligand-regulated co-localization (as proposed) but also, simultaneously, direct interactions via fluorescence resonance energy transfer techniques. With this combined approach, we studied the effects of a spectrum of existing and novel SERMs on the co-localization and interactions of ERalpha with ERbeta and with itself. We found a distinct deficiency in the ability of the soy SERM genistein to promote ERalpha interaction with itself, but not with ERbeta. Other SERMs including raloxifene, ICI182780, tamoxifen, 4-hydroxy-tamoxifen and four chemical derivatives of tamoxifen behaved exactly like estradiol in these assays. A derivative of genistein behaved exactly like genistein. Most importantly, another chemical derivative of genistein behaved like estradiol and the remaining SERMs. This work is now being written for publication. Thus, techniques were developed that distinguished the ligand-specific interactions regulated by existing and novel SERMs in living cells. We look forward to expanding these studies to a broader spectrum of interactions to characterize the precise similarities and differences in the molecular interactions of different SERMs.