Cyclin-dependent kinase 4 (CDK4) has been implicated as a potential new therapeutic target in women with breast cancers that overexpress ERBB2 and cyclin D1.

CDK4 regulates cell-cycle progression by interacting with the D-type cyclins and phosphorylating and inhibiting the retinoblastoma protein (RB). Cyclin D1 is overexpressed in many cancers, including most breast cancers, and loss of this protein is known to suppress mammary carcinogenesis in mouse models. However, whether this is dependent on the kinase activity of the cyclin D1–CDK4 complex or on cyclin-D1 kinase-independent functions was unclear, so Yu and colleagues investigated.

To check whether CDK4 activity was required for breast development, the authors used a mouse model in which cleared mammary fat pads were transplanted with either Cdk4-null mammary epithelium or wild-type mammary epithelium. All of the transplanted mice developed normal breast architecture during pregnancy and were able to lactate, supporting the previous finding that expression of cyclin D1 is not required for breast development.

To investigate the function of CDK4 in breast tumorigenesis, the authors crossed Cdk4-null mice with mice expressing the oncogene Erbb2 under the control of the mouse mammary tumour virus promoter. They found that loss of CDK4 inhibited breast tumour development.

As well as inactivating RB, cyclin D1–CDK4 complexes sequester p27 from cyclin E–CDK2 complexes to enable cell-cycle progression. To investigate whether this function was important for tumorigenesis, the authors collaborated with Landis and colleagues to produce cyclin-D1 knock-in mice that express a cyclin-D1 mutant protein that is still able to interact with CDK4 and so sequester p27, but the complex has no kinase activity. These mice were also resistant to Erbb2-driven mammary tumorigenesis, indicating that it is the kinase activity of this complex that is required to induce Erbb2 breast tumours. Yu and colleagues also used RNA interference to show that CDK4 kinase activity is required to maintain the tumours as well as initiate them.

Does this model hold true in human breast cancer? By analysing protein expression levels in 70 sections of human breast tumours that overexpress ERBB2, the authors found that 27% showed increased expression of cyclin D1. Because most tissues develop normally in both Cdk4-null and cyclin D1-null mice, the authors suggest that CDK4 might prove to be a selective therapeutic target in all tumours that overexpress ERBB2.