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.
Phytonutrients Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705, USA. wangt@ba.ars.usda.gov
Thomas T Y
TT
Wang
Matthew J
MJ
Milner
John A
JA
Milner
Young S
YS
Kim
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