SPECIFIC ROLES FOR D-CYCLINS IN ONCOGENESIS

Dana-Farber Cancer Institute, Boston MA

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Abstract

D-type cyclins (cyclin D1, D2 and D3) are the ultimate recipients of all mitogenic and oncogenic signals. Aberrant expression of D-cyclins is seen in many human malignancies and virtually all human cancers contain lesions in pathways impacting on D-cyclins. We have generated knockout mouse strains lacking cyclin D1, D2 or D3 using homologous recombination in embryonal stem cells. All three strains are viable and display focused, tissue-specific phenotypes. In the proposed work we will use these mice as a tool to study the role of D-cyclins in tumorigenesis. In the first Specific Aim we will ask whether the loss of cyclin D1 renders mice resistant to breast cancers induced by various oncogenes. Cyclin D1 is overexpressed in the majority of human breast cancers. Importantly, overexpression of cyclin D1 is believed to play a causative role in tumorigenesis, as agents that neutralize cyclin D1 function were shown to shut off the proliferation of breast cancer cells in vitro. Cyclin D1 is normally expressed in nearly all human tissues and, until recently, was thought to be indispensable for proliferation of all cell lineages. However, our unexpected finding that in adult cyclin D1-/- mice the consequences of cyclin D1-ablation are restricted to mammary epithelium, raises the possibility that a specific, anti-cyclin D1 therapy for human breast cancers might be highly selective in shutting off the proliferation of tumor cells while sparing other tissues. As a first step towards this goal we wish to test if the ablation of cyclin D1 prevents cancer formation in vivo. In the second Specific Aim we will take advantage of fibroblasts lacking cyclin D1, D2 or D3 to study the dependence of various oncogenic signal transduction pathways on different D-cyclins at the cellular and molecular level. The studies described in the third Specific Aim take advantage of recently-generated cyclin E greater than D1 "knock-in" mice. In this strain we have deleted the coding exons of cyclin D1 and replaced them by cyclin E cDNA. Analyses of these mice have demonstrated that cyclin E can replace cyclin D1 in driving normal cell proliferation and rescue the phenotypic manifestations of cyclin Dl-deficiency. In this Specific Aim we will ask whether cyclin E can replace cyclin D1 in driving oncogenic growth of cancer cells.