Indole-3-carbinol (I3C), a co
mponent of
Brassica vegetables, is under study as a preventiveagent of cancers of the breast and other organs. Following ingestion, I3C is converted to a series ofoligo
meric products that presu
mably are responsible for the in vivo effects of I3C. We report the effectsof the
major tri
meric product, 5,6,11,12,17,18-hexahydrocyclonona[1,2-
b:4,5-
b':7,8-
b' ']triindole (CTr),on the estrogen receptor (ER) signaling pathways. Tu
mor-pro
moting effects of high doses of I3C
may bedue to activation of aryl hydrocarbon receptor (AhR)-
mediated pathways; therefore, we also exa
minedthe effects of CTr on AhR activated processes. We observed that CTr is a strong agonist of ER function.CTr sti
mulated the proliferation of estrogen-responsive MCF-7 cells to a level si
milar to that produced byestradiol (E
2) but did not affect the growth of the estrogen-independent cell line, MDA-MD-231. CTrdisplaced E
2 in co
mpetitive-binding studies and activated ER-binding to an estrogen responsive DNAele
ment in gel
mobility shift assays with EC
50s of about 0.1
mages/entities/
mgr.gif">M. CTr activated transcription of an E
2-responsive endogenous gene and exogenous reporter genes in transfected MCF-7 cells, also with highpotency. CTr failed to activate AhR-
mediated pathways, consistent with the low-binding affinity of CTrfor the AhR reported previously. Co
mparisons of the confor
mational characteristics of CTr with other ERligands indicated a re
markable si
milarity with ta
moxifen, a selective ER antagonist used as a breast cancertherapeutic agent and suggest an excellent fit of CTr into the ligand-binding site of the ER.