Researchers say that they have identified a previously unsuspected protein as a key player in the resistance to estrogen-targeting breast cancer therapies.
The scientists used a loss-of-function RNAi screening method to identify genes that when silenced cause tamoxifen resistance. The researchers identified cyclin-dependent kinase 10 (CDK10) as a critical component of the response to tamoxifen and other treatments that target estrogen signaling.
Examination of signaling molecules downstream of CDK10 led the authors to propose that CDK10 normally represses the ETS2 transcription factor and that the loss of CDK10 expression results in relief of ETS2 repression and upregulation of c-RAF transcription. Enhanced c-RAF results in the triggering of mitogen-activated protein kinase and increased cyclin D1 expression, both previously linked to tamoxifen resistance.
Importantly, the researchers also found that in patients treated with tamoxifen, drug resistance occurred significantly earlier in those with tumors that express low levels of CDK10. Furthermore, methylation of the CDK10 gene also correlated with resistance.
The investigators for this research were from the Breakthrough Breast Cancer Research Centre, Ospedale Santa Croce e Carle, and King’s College London School of Medicine. The study will be published in the February issue of Cancer Cell.