Indole-3-carbinol triggers aryl hydrocarbon receptor-dependent estrogen receptor (ER)alpha protein degradation in breast cancer cells disrupting an ERalpha-GATA3 transcriptional cross-regulatory loop.
Estrogen receptor (ER)alpha is a critical target of therapeutic strategies to control the proliferation of hormone-dependent breast cancers. Preferred clinical options have significant adverse side effects that can lead to treatment resistance due to the persistence of active estrogen receptors. We have established the cellular mechanism by which indole-3-carbinol (I3C), a promising anticancer phytochemical from Brassica vegetables, ablates ERalpha expression, and we have uncovered a critical role for the GATA3 transcription factor in this indole-regulated cascade. I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERalpha protein. I3C inhibits endogenous binding of ERalpha with the 3'-enhancer region of GATA3 and disrupts endogenous GATA3 interactions with the ERalpha promoter, leading to a loss of GATA3 and ERalpha expression. Ectopic expression of GATA3 has no effect on I3C-induced ERalpha protein degradation but does prevent I3C inhibition of ERalpha promoter activity, demonstrating the importance of GATA3 in this I3C-triggered cascade. Our preclinical results implicate I3C as a novel anticancer agent in human cancers that coexpress ERalpha, GATA3, and AhR, a combination found in a large percentage of breast cancers but not in other critical ERalpha target tissues essential to patient health.
Marconett
Crystal N
CN
Department of Molecular and Cell Biology, University of California-Berkeley, CA 94720, USA.
Sundar
Shyam N
SN
Poindexter
Kevin M
KM
Stueve
Theresa R
TR
Bjeldanes
Leonard F
LF
Firestone
Gary L
GL
D015153:Blotting, Western; D001937:Brassica; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D007211:Indoles / Q000737:chemistry*; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry
D047628:Estrogen Receptor alpha; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D007211:Indoles; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D025801:Ubiquitin; C016517:indole-3-carbinol