Evaluation of GPR30 a Novel Estrogen Receptor for Assessing Responsiveness to Anti-Estrogen Therapy

摘要

Antiestrogens are the most effective and widely administered therapy for the management of breast cancer. Their efficacy has been attributed to their ability to antagonize the estrogen receptor, and the presence of ER in breast tumor biopsy specimens correlates well with responsiveness to antiestrogen therapy. Still, one in four patients with ER-positive tumors do not respond to antiestrogens, while one in six patients with ER-negative breast tumors undergo objective tumor regression following antiestrogen therapy (Witliff, 1934). These clinical observations suggest that alternative mechanisms of estrogen action may regulate the growth and survival of breast tumors. We have provided evidence that estrogen acts independently of the known estrogen receptors, ERalpha and ER%, via the G- protein coupled receptor, GPR3O, to regulate the EGFR-to-MAP K signaling axis (Filardo et al, 2000; reviewed in Filardo, 2001; Filardo et al, 2001). Moreover, we have shown that the antiestrogens, tamoxifen and faslodex (ICI 182, 780), also trigger GPR30- dependent regulation of this HE-EGF autocrine loop. Dysregulation of the EGFR-to-MAP K signaling axis is a common occurrence in breast cancer (Slamon et al, 1989, Sivaraman et al, 1997). The subject of this DOD award is to investigate the relationship between GPR30 expression and MAP K activity in breast tumor biopsy specimens obtained at first diagnosis or following antiestrogen or other adjuvant therapies. The results of these studies may lead to a further refinement in assessing responsiveness to antiestrogen therapy.