05 FEBRUARY 2008
CDK10 is an Important Determinant of Resistance to EndocrineTherapy
Scientists at the Breakthrough Breast Cancer Research Centre have identified how some breast cancers may become resistant to hormone treatments like tamoxifen. The study, published in the February issue of Cancer Cell, shows for the first time that a protein called CDK10 is able to control the development of tamoxifen resistance in hormone sensitive breast cancer, and has potentially important implications in the treatment of women with this form of the disease.
Therapies that target oestrogen signalling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. In this study, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. The scientists demonstrated that CDK10 is an important determinant of resistance to endocrine therapies and showed that CDK10 silencing increases ETS2-driven transcription of c-RAF. This leads to activation of downstream components of the MAPK pathway and increase in Cyclin D1 expression, resulting in loss of tumour cell reliance upon oestrogen signalling.
Patients with ERĪ±-positive tumours that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumours.
Identification of CDK10 as an Important Determinant of Resistance to Endocrine Therapy for Breast Cancer. Iorns et al. Cancer Cell, Vol 13, 91-104, 05 February 2008
Therapies that target oestrogen signalling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. In this study, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. The scientists demonstrated that CDK10 is an important determinant of resistance to endocrine therapies and showed that CDK10 silencing increases ETS2-driven transcription of c-RAF. This leads to activation of downstream components of the MAPK pathway and increase in Cyclin D1 expression, resulting in loss of tumour cell reliance upon oestrogen signalling.
Patients with ERĪ±-positive tumours that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumours.
Identification of CDK10 as an Important Determinant of Resistance to Endocrine Therapy for Breast Cancer. Iorns et al. Cancer Cell, Vol 13, 91-104, 05 February 2008
