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

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 (ER alpha). 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 ER alpha reversed the I3C mediated loss of IGF1 R and IRS1 gene expression demonstrating that down-regulation of ER alpha is functionally linked to I3C control of IGF1R and IRS1 expression. I3C disrupted binding of endogenous ER alpha, but not Sp1, to ERE-Sp1 composite elements within the IGF1R/IRS1 promoters. Exogenous ER alpha 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 ER alpha-mediated transcription of cell signaling components within the IGF1 cascade. (C) 201 2 Elsevier Ireland Ltd. All rights reserved.