2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds induce a b
road spectrum of biochemical and toxic responses and disrupt multiple endoc
rine pathways. Research in this laboratory has focused on characterizing ar
yl hydrocarbon receptor (AhR)-mediated antiestrogenicity in the rodent uter
us and mammary and in human breast cancer cells. TCDD inhibits multiple est
rogen (E2)-induced responses in these tissues including development or grow
th of human mammary and endometrial cancer cells, carcinogen-induced mammar
y cancer in rats, and mammary cancer in mice bearing breast cancer cell xen
ografts. The mechanisms of AhR-mediated antiestrogenicity are complex; howe
ver, studies on the molecular biology of cross-talk between the AhR and est
rogen-receptor (ER) signaling pathways have been initiated using several E2
-regulated genes as models. The results indicate that the nuclear AhR compl
ex targets specific genomic core inhibitory-dioxin responsive elements (iDR
Es) in promoter regions of some E2-responsive target genes to inhibit hormo
ne-induced transactivation. The pS2, cathepsin and c-fos genes have functio
nal iDREs, whereas the iDRE in the progesterone receptor gene promoter was
not functional. Research has also focused on development of AhR-based antie
strogens which inhibit mammary tumor development and growth but do not exhi
bit prototypical AhR-induced toxic responses. (C) 1998 Elsevier Science Ire
land Ltd. All rights reserved.