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

• Published in: Molecular and cellular endocrinology Vol. 363; no. 1-2; pp. 74 - 84
• Main Authors: Marconett, Crystal N., Singhal, Ankur K., Sundar, Shyam N., Firestone, Gary L.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 05.11.2012
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Base Sequence; Breast Neoplasms; cell cycle; Cell Proliferation - drug effects; Conserved Sequence; Dose-Response Relationship, Drug; Estradiol - pharmacology; Estradiol - physiology; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - physiology; Estrogen receptor-alpha; Estrogens - pharmacology; Estrogens - physiology; Female; G1 Phase Cell Cycle Checkpoints - drug effects; gene expression; Gene Expression - drug effects; Gene Expression Regulation, Neoplastic; glucobrassicin; Hormone sensitive breast cancer; Humans; hydrolysis; Indole-3-carbinol; Indoles - pharmacology; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Insulin Receptor Substrate-1; insulin receptors; insulin-like growth factor I receptor; Insulin-like Growth Factor-1 Receptor; MCF-7 Cells; Molecular Sequence Data; neoplasm cells; Promoter Regions, Genetic; Protein Binding; protein degradation; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Signal Transduction; somatomedins; vegetables; Insulin Receptor Substrate-1; ERα; IRS1; Estrogen receptor-alpha; I3C; Indole-3-carbinol; Hormone sensitive breast cancer; IGF1R; Insulin-like Growth Factor-1 Receptor
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2012.07.008

► Disruption of IGF1R and IRS1 expression is a new I3C anti-proliferative pathway. ► I3C arrests breast cancer cell proliferation by ablating IGF1R and IRS1 expression. ► I3C down-regulation of ERα triggers the loss of IGF1R and IRS1 gene expression. ► I3C disrupts the interactions of endogenous ERα with composite ERE-Sp1 DNA elements. ► I3C represents a potential anti-cancer therapeutic for estrogen sensitive cancers. 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.