Insulin-like growth factor-I inhibits growth regulatory responses engaged by estrogen and progesterone in the mouse mammary gland

The pathways and key players that regulate parity-induced protection against breast cancer, conferred by estrogen (E) and progesterone (P), have not fully been explained. Interestingly, in rodents, high levels of circulating insulin-like growth factor-I (IGF-I) appear to block this parity-induced protection. Using an in-vitro mouse mammary gland whole organ culture system, we investigated the mechanisms by which IGF-I affects the protective effects of E+P. Earlier studies have demonstrated that important changes induced by parity include both the enhanced sensitivity to p53 activation, and the cell death that occurs in response to DNA damage. Remarkably, when IGF-I was added to cultures containing E+P and irradiated, both cell death and expression of the tumor suppressor protein p53 were inhibited (P\u3c0.03 and \u3c0.006, respectively). In addition, quantitative real-time PCR analysis of numerous genes identified by microarray as being upregulated in response to prolonged exposure to pregnancy levels of E+P suggested that a subset was affected by the addition of IGF-I. IGF-I suppressed the hormone-induced expression of insulin-like growth factor-binding protein-3, transforming growth factor beta-1, and cellular retinol-binding protein-1 (P\u3c0.01 for all genes); all of which are genes that are important in growth suppression and the regulation of survival of cells. Overall, the observed reductions in p53 sensitivity and hormone-induced gene expression in response to IGF-I in vitro suggest a mechanism for the blockade in parity-induced protection previously seen in response to IGF-I in vivo