Insulin Like Growth Factor I Receptor Function in Estrogen Receptor Negative Breast Cancer. Addendum

摘要

The mammary gland is unique in that it grows and develops throughout the lifetime of a reproductive female and ovarian steroids play a central role in this growth and development. Estrogens are responsible primarily for stimulating ductal and stromal proliferation, The effects of estrogens are due, in part, to their ability to induce the local synthesis of growth factors such as insulin like growth factor-I (IGF-I). In turn, IGF-I activates ER-alpha through a hormone independent mechanism, however, the precise mechanism as well as the signal transduction pathways involved in the cross talk between IGF-I and ER-alpha are poorly defined. In fact, the ras-MAPK and the PI3K-AKT pathways has been shown-to mediate the effects of IGF-I on ER-alpha activity. The original proposal was to test the hypothesis that the downstream mediator of these pathways is p70/S6 kinase. However, early results showed that the effects of IGF-I were not mediated by p70/S6 kinase. The revised aim was to test the hypothesis that the effects of IGF-I were mediated through the activation of nitric oxide synthetase by Akt. Preliminary results show that nitrite and nitrates, the breakdown products of nitric oxide, activate ER-alpha suggesting that the effects of IGF-I are mediated, in part, by activation of nitric oxide synthetase.