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: Crystal N Marconett, Ankur K Singhal, Shyam N Sundar, Gary L Firestone
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 363 Issue 1-2 Pg. 74-84 (Nov 05 2012) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 22835548 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• ESR1 protein, human
• Estrogen Receptor alpha
• Estrogens
• IRS1 protein, human
• Indoles
• Insulin Receptor Substrate Proteins
• Estradiol
• indole-3-carbinol
• Receptor, IGF Type 1

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Base Sequence
• Breast Neoplasms
• Cell Proliferation (drug effects)
• Conserved Sequence
• Dose-Response Relationship, Drug
• Estradiol (pharmacology, physiology)
• Estrogen Receptor alpha (antagonists & inhibitors, physiology)
• Estrogens (pharmacology, physiology)
• Female
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression (drug effects)
• Gene Expression Regulation, Neoplastic
• Humans
• Indoles (pharmacology)
• Insulin Receptor Substrate Proteins (genetics, metabolism)
• MCF-7 Cells
• Molecular Sequence Data
• Promoter Regions, Genetic
• Protein Binding
• Receptor, IGF Type 1 (genetics, metabolism)
• Signal Transduction