title: Indole-3-carbinol disrupts estrogen receptor-alpha dependent expression of insulin-like growth factor-1 receptor and insulin receptor substrate-1 and proliferation of human breast cancer cells.
abstract: We previously established that Indole-3-Carbinol (I3C), a natural hydrolysis product of glucobrassicin in cruciferous vegetables, arrests the proliferation of estrogen-dependent human breast cancer cells and induces protein degradation of Estrogen Receptor-alpha (ERα). We demonstrate in human MCF-7 breast cancer cells that I3C ablates expression of Insulin-like Growth Factor Receptor-1 (IGF1R) and Insulin Receptor Substrate-1 (IRS1), downstream effectors of the IGF1 signaling pathway. Exogenous ERα reversed the I3C mediated loss of IGF1R and IRS1 gene expression demonstrating that down-regulation of ERα is functionally linked to I3C control of IGF1R and IRS1 expression. I3C disrupted binding of endogenous ERα, but not Sp1, to ERE-Sp1 composite elements within the IGF1R/IRS1 promoters. Exogenous ERα abrogated, and combined expression of IGF1R and IRS1 attenuated, the I3C mediated cell cycle arrest. Therefore, I3C inhibits proliferation of estrogen-sensitive breast cancer cells through disruption of ERα-mediated transcription of cell signaling components within the IGF1 cascade.
authors: Department of Molecular and Cell Biology, The Cancer Research Laboratory, University of California, Berkeley, CA 94720-3200, USA.
authors: Crystal N
authors: CN
authors: Marconett
authors: Ankur K
authors: AK
authors: Singhal
authors: Shyam N
authors: SN
authors: Sundar
authors: Gary L
authors: GL
authors: Firestone
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001483:Base Sequence; D001943:Breast Neoplasms; D049109:Cell Proliferation / Q000187:drug effects*; D017124:Conserved Sequence; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C526292:IRS1 protein, human; D007211:Indoles; D055504:Insulin Receptor Substrate Proteins; D004958:Estradiol; C016517:indole-3-carbinol; D017526:Receptor, IGF Type 1