) Many compounds used in our industrial society, including insecticides, plasticizers, dioxins, and other xenobiotics, can be classified as """"""""environmental estrogens."""""""" Recent clinical epidemiological studies are split as to whether environmental estrogens contribute to the observed increases in breast cancer incidence. Key to understanding the relationship of environmental estrogens to breast cancer is their mechanism of action whether they act directly through the estrogen receptor or whether they produce estrogen-like effects and alter breast cell biology by other mechanisms. It is critical to know whether compounds that bind to estrogen receptor poorly still have estrogenic effects. Also, there is a need for a more effective way to screen compounds for estrogenic and anti-estrogenic effects on the human breast. This pilot project addresses these issues by focusing on model non-steroidal estrogens, the Doisynolic/Allenolic compounds. Like the multitude of potential environmental estrogens they represent, these compounds demonstrate potent biological effects, yet bind to estrogen receptor poorly. Also they have a distinct history of differing potencies in humans versus animal species. Thus, they are ideally positioned to address these important and current issues regarding environmental estrogens and breast cancer etiology. The applicant's goal is to test the hypothesis that Doisynolic/Allenolic acids, in spite of low affinity for estrogen receptor, mediate their estrogenic effects through the classic estrogen receptor. We will use assays for each of the molecular functions of estrogen receptor. In addition, the applicant will determine the receptor dependence for each mechanism of gene regulation. The applicant will evaluate both estrogen receptor mediated and estrogen receptor independent mechanisms using human breast cell lines to compare compounds to 17 beta-estradiol on both the activation and repression of endogenous genes. Finally, the applicant will specifically test explanations of the apparent paradox these compounds exhibit, high biological activity with low receptor affinity. By exploring these compounds and the apparent paradox they present, increased understanding of the mechanisms of action of non-steroidal environmental estrogens will be gained. This pilot project will validate these molecular approaches for defining estrogenic activity, first for our model compounds and, in the future, for evaluation of other chemicals. All of these goals have a direct relationship to the etiology of breast cancer and the actions of chemicals and hormones.
| Adler, Molly; Hou, Yuqing; Sandrock, Paul et al. (2006) Derivatives of Z-bisdehydrodoisynolic acid provide a new description of the binding-activity paradox and selective estrogen receptor modulator activity. Endocrinology 147:3952-60 |
| Meyers, Cal Y; Hou, Yuqing; Winters, Todd A et al. (2002) Activities of a non-classical estrogen, Z-bis-dehydrodoisynolic acid, with ERalpha and ERbeta. J Steroid Biochem Mol Biol 82:33-44 |
| Meyers, C Y; Hou, Y; Robinson, P D et al. (2000) Absolute structure determination of the highly biologically active bisdehydrodoisynolic acids. J Pharm Sci 89:513-8 |
| Meyers, C Y; Lutfi, H G; Adler, S (1997) Transcriptional regulation of estrogen-responsive genes by non-steroidal estrogens: doisynolic and allenolic acids. J Steroid Biochem Mol Biol 62:477-89 |
