Estrogen receptor alpha as a target for indole-3-carbinol.
A wealth of preclinical evidence supports the antitumorigenic properties of indole-3-carbinol (I3C), which is a major bioactive food component in cruciferous vegetables. However, the underlying molecular mechanism(s) accounting for these effects remain unresolved. In the present study, estrogen receptor alpha (ER-alpha) was identified as a potential molecular target for I3C. Treating MCF-7 cells with 100 microM I3C reduced ER-alpha mRNA expression by approximately 60% compared to controls. This reduction in ER-alpha transcript levels was confirmed using real-time polymerase chain reaction. The I3C dimer, 3,3'-diindolylmethane (DIM), was considerably more effective in depressing ER-alpha mRNA in MCF-7 cells than the monomeric unit. The suppressive effects of 5 microM DIM on ER-alpha mRNA was comparable to that caused by 100 microM I3C. DIM is known to accumulate in the nucleus and is a preferred ligand for aryl hydrocarbon receptor (AhR) to I3C. The addition of other AhR ligands, alpha-naphthoflavone (alpha-NF, 10 microM) and luteolin (10 microM), to the culture media resulted in a similar suppression in ER-alpha mRNA levels to that caused by 5 microM DIM. Thus, it is likely that the binding of ligands to AhR inhibits nuclear ER-alpha transcript. The results from these experiments suggest that the antitumorigenic effects of I3C in MCF-7 human breast cancer cells may arise from its ability to reduce ER-alpha expression through the binding of its metabolite, DIM, to the nuclear AhR.
Wang
Thomas T Y
TT
Phytonutrients Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705, USA. wangt@ba.ars.usda.gov
Milner
Matthew J
MJ
Milner
John A
JA
Kim
Young S
YS
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001571:Benzoflavones / Q000494:pharmacology; D001943:Breast Neoplasms; D002452:Cell Count; D045744:Cell Line, Tumor; D018076:DNA, Complementary; D019281:Dimerization; D047628:Estrogen Receptor alpha / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047311:Luteolin / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism; D014675:Vegetables / Q000737:chemistry
D016588:Anticarcinogenic Agents; D001571:Benzoflavones; D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; D007211:Indoles; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C011512:alpha-naphthoflavone; C016517:indole-3-carbinol; D047311:Luteolin; C016392:3,3'-diindolylmethane