Role of IGF-II in Mammary Tumorigenesis and its Modulation by TIMP-1

摘要

Generation and characterization of MMTV-IGF-II transgenic mice revealed that overexpression of IGF-II affects both mammary epithelial apoptosis and proliferation in vivo. IGF-II overexpression inhibited mammary epithelial apoptosis during postlactational involution suggesting that multiple rounds of lactation/involution in the presence of high IGF-II could lead to incomplete involution. In fact, areas of focal epithelial hyperplasia in multiparous transgenic mice have been observed and this aspect is being investigated further. In addition, IGF-II overexpression inhibited mammary epithelial proliferation and this effect appeared to be mediated through IGF-II's ability to increase the levels of the tumor suppressor, PTEN. Thus in normal mammary epithelial cells elevated levels of IGF-II may induce PTEN expression to control the mitogenic and antiapoptotic effects of IGF-II. It is possible that loss of the link between IGF-II and ETEN is one event that occurs prior to IGF-II- induced mammary tumorigenesis. Our preliminary findings support this idea in that we found that PTEN mRNA levels are reduced in MMTV-IGF-II-induced mammary tumors. Finally, IGF-II overexpression driven by the MMTV promoter produced tumors in a number of other organs including the lung and uterus and thus the effects of IGF-II on tumorigenesis in other organs can be explored using this model.