Cyclin D1 and mammary carcinoma: new insights from transgenic mouse models

Breast cancer is a heterogeneous disease arising from multiple genetic changes in oncogenes and tumour suppressor genes with pivotal roles in the homeostatic control of mammary epithelial cell proliferation, differentiation and death. Aberrations in the expression and function of these genes lead to clonal expansion with subsequent acquisition of invasive and metastatic phenotypes.An increasing number of genes have been implicated in the evolution of breast cancer, and this list is expected to expand with the development of new genomics tools. Studies to date have relied on correlations between gene mutation, gene expression and breast cancer phenotype to identify candidate genes, with demonstration of function dependent on mechanistic studies in diverse experimental systems. One powerful model system is the genetically modified mouse where several genes induce mammary carcinoma when expressed alone or in combination.In a major recent advance, the laboratory of Piotr Sicinski has combined transgenic and targeted gene deletion approaches to address the requirement for the cell cycle oncoprotein, cyclin D1, in the induction of mammary carcinoma [1]. These novel data demonstrate that cyclin D1 is essential for the development of mammary cancers induced by c-neu and v-Ha-ras, but not those induced by c-myc or Wnt-1. This is the first genetic evidence of an absolute requirement for cyclin D1 in the formation of a subset of mammary cancers, and supports an expanding literature implicating this oncoprotein in the evolution of human breast cancer.Cyclin D1 is the product of the CCND1 gene and was first implicated in tumourigenesis following localisation to chromosome 11q13 [2], a region of the genome that is commonly amplified in a range of human carcinomas including breast cancer [3]. Cyclin D1 plays a pivotal role in the regulation of progression from the G1 to the S phase of the cell cycle through the formation of active enzyme complexes with cyclin-dependent kinases Cdk