Mechanisms for c-Myc-Induced, TGF - Prevented Mouse Mammary Tumors

摘要

Many clinical studies have shown that apoptosis may be related to various pathological parameters of breast cancer, such as tumor size, histologic features, metastasis and survival. Over 50% of human breast cancer biopsies show amplification or overexpression of c-myc, an oncogene that is known to play a crucial role in cell proliferation, apoptosis, and transformation. Female c-myc transgenic mice also develop mammary cancer that is characterized by a large number of apoptotic cells, thus serving as a good in vivo model for study on the role of c- Myc in both mammary carcinogenesis and apoptosis. On the other hand, TGFalpha, a growth factor also frequently overexpressed in human breast cancer, has been shown in MT-tgfa/MMTV-c-myc double transgenic mice to enhance c-Myc-induced mouse mammary carcinogenesis, probably in part by blocking apoptosis. Our proposal set out to examine the c- Myc mechanisms of mediated apoptosis in our mouse mammary tumor model. In addition, we examined the survival-promototing effect of the TGFalpha-EGF receptor pathway in this model. We initially provided evidence for TGFalpha-EGF receptor-mediated cell survival by a calcium/calmodulin mediated pathway regulating Akt Subsequent studies have focused on the role of a recently discovered kinase, PNCK, and p55gamma, a p13 kinase subunit, to mediate the EGF survival signal.