Dysregulation of the cyclin D1:CDK4/6 axis appears to be an early step in breast cancer pathogenesis given that 'overexpression' of cyclin D1 is frequently found as early as ductal carcinoma in situ and maintained in metastatic lesions but is absent in the earliest lesions such as atypical ductal hyperplasias [44, 45]. This evidence concerns the gene CCND1 and ductal breast carcinoma in situ.