Unique Role for Cyclin D1 in Mammary Gland Oncogenesis and Development

摘要

The majority of human breast cancers overexpress cyclin Dl. We previously generated mice lacking cyclin Dl using gene targeting. These mice develop essentially normally, revealing that cyclin Dl is dispensable for proliferation of the vast majority of lineages. These findings suggest that targeting of cyclin Dl might be highly specific in shutting off the growth of breast cancer cells, while sparing other tissues. As a first step towards an anti-cyclin Dl therapy, we studied breast cancer susceptibility of cyclin Dl- deficient mice. We found that these mice are resistant to breast cancers induced by Neu and Ras oncogenes, while being sensitive to other mammary epithelial oncogenic pathways. Our analyses revealed that in mammary epithelial cells, the Neu-Ras pathway is connected to the cell cycle machinery via cyclin Dl, explaining the absolute dependency on cyclin Dl for malignant transformation in mammary glands. Our results suggest that an anti-cyclin Dl therapy might be highly specific in treating human breast cancers with hyperactivated Neu-Ras pathway.