Decreased expression of the mannose 6- phosphate/insulin-like growth factor-II receptor promotes growth of human breast cancer cells

In this study, using viral and ribozyme strategies we reduced the expression of M6P/IGF2R in human breast cancer cells and then examined the effect on growth and apoptosis of these cells.Our results showed that infection of MCF-7 cells with the adenovirus carrying a ribozyme targeted against the M6P/IGF2R mRNA dramatically reduced the level of transcripts and the functional activity of M6P/IGF2R in these cells. Accordingly, cells treated with the ribozyme exhibited a higher growth rate and a lower apoptotic index than control cells (infected with a control vector). Furthermore, decreased expression of M6P/IGF2R enhanced IGF-II-induced proliferation and reduced cell susceptibility to TNF-induced apoptosis.These results suggest that M6P/IGF2R functions as a growth suppressor and its loss or mutation may contribute to development and progression of cancer. This study also demonstrates that adenoviral delivery of the ribozyme provides a useful tool for investigating the role of M6P/IGF2R in regulation of cell growth.With one million new cases each year, breast cancer is the most common cancer among women and is the leading cause of death in women 30 to 70 years of age in the world. Breast cancer results from genetic and environmental factors including diet, radiation and hormones [1-5]. The molecular events involved in breast carcinogenesis, however, remain to be elucidated.Numerous studies have shown that polypeptide growth factors such as insulin-like growth factors (IGFs) are mitogens for breast cancer cells [6-9]. The IGF-I and IGF-II signal through a common tyrosine kinase receptor, the insulin-like growth factor 1 receptor (IGF1R), and have mitogenic and cell survival actions that may promote tumor development. Modulation of this mitogenic pathway occurs in part via the M6P/IGF2R, which functions in the internalization and degradation of IGF-II [10]. M6P/IGF2R is also important in activation of TGF-β, a potent growth inhibitor for most cell types, and in binding,