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

The bioavailability of IGF-II, a molecule implicated in breast tumorigenesis, was recently shown by our laboratory to be modulated by TlMP-1 through controlling MM P-mediated IGFBP degradation. To investigate the exact role of IGF-II in breast tumorigenesis and examine IGF-II mediated events potentially regulated by TIMP-I expression we generated independent MMTV-IGF-II transgenic mice. Since increased proliferation andor decreased apoptosis precede tumor development, we investigated the effects of IGF-II overexpression on proliferation during mammary development and its effect on apoptosis during postlactation involution. We found that elevated levels of IGF-II inhibitied mammary epithelial proliferation in vivo. The delay in ductal morphogenesis correlated with an elevation of the phosphatase PTEN, in the transgenic tissue. Higher PTEN levels resulted in reduced phosphorylation of AktPKB and a subsequent reduction in cylcin DI protein levels. We have also observed a delay in ductal morphogenesis when the oncogene, erbB2 is overexpressed. IGF-II overexpression also affected epithelial apoptosis in vivo. Specifically, high levels of IGF-II resulted in delayed postlaction involution through inhibiting mammary epithelial apoptosis. This inhibition of apoptosis was associated with a sustained phosphorylation of AktPKB in the transgenic tissue. These data demonstrate that an elevation IGF-II can affect the pre-tumoriqenic events, events potentially controllable through manipulating TIMP-I.