The role of cyclin D1 in cancer

Abstract

Cyclin D1 protein levels are elevated by mitogenic and oncogenic signaling pathways as cyclin D1 protein is rate-limiting for G1-phase cell cycle progression in many cell types as well as over-expressed in 20--30% of human breast cancers and elevated in human adenomatous polyps of the colon. Based on my hypothesis that the cyclin D1 protein is a critical downstream factor required in the initiation and progression of breast and colon cancers, I undertook investigations as to the oncogenic mechanism and requirement of cyclin D1 in the onset and progression of these diseases.;Caveolin-1 is deleted in human cancers including breast tumors where it is also found mutated in approximately 16% of human breast cancers. Using the cyclin D1 promoter as a molecular probe to assay transcriptional events which regulate G1 progression, I found that cyclin D1 is regulated by caveolin-1 expression in a negative manner and that maximal inhibition of the cyclin D1 promoter was dependent on a T-cell factor/lymphoid enhancer factor-1 (TCF/LEF-1) response element in the cyclin promoter. Using transgenic and knockout mice to assess the specific role for p27Kip1 in neu-induced tumorigenesis, I identified p27Kip1 as being haplo-insufficient for neu-induced mammary tumor suppression in vivo and that inhibition of p27Kip1 function may be due in part to its down regulation by Skp2 and redistribution away from cyclin E and into cyclin D1 complexes.;I have also examined the specific requirement of cyclin D1 in intestinal tumorigenesis. Mutations in the Apc tumor-suppressor gene are among the earliest events in colon cancer and subsequent activation of the Wnt pathway specifically targets and induces cyclin D1 expression. Using the ApcMin mouse model of human colorectal cancer, I found that reduction of cyclin D1 protein abundance in the presence of constitutive beta-catenin/Tcf4-signaling increased cellular differentiation decreased DNA synthesis and importantly, reduced intestinal polyp formation.;These studies identify cyclin D1 as a critical signaling target in both mammary and intestinal tumorigenesis. By understanding how cyclin D1 is regulated and the precise molecular functions associated with the protein, I aim to provide a rational basis for molecular approaches to inhibit cellular transformation.