Poster Presentation 25th Lorne Cancer Conference 2013

Characterization of molecular features of MYC dependence and identification of a synthetic lethal interaction between MYC and CDK1 in human breast cancer cells (#226)

Jian Kang 1 , Robert L Sutherland 1 , Elizabeth A Musgrove 1
  1. Garvan Institute of Medical Research, Sydney, NSW, Australia

The MYC oncogene contributes to human breast tumour formation and development. More than 40% of breast tumours overexpress MYC protein. Inhibition of MYC is therefore an attractive therapeutic approach for breast cancer treatment. However, this transcription factor has no obvious druggable domains, rendering the identification of small molecule inhibitors a challenge. With the aim of investigating new therapeutic strategies for treatment of MYC-driven breast cancer, we firstly characterized the molecular features of MYC dependence in breast cancer cells. By using small interfering RNA (siRNA), MYC expression was reduced in 26 human breast cancer cell lines and cell proliferation was evaluated by BrdU assay. Breast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC mRNA and protein expression levels. HER2 positive breast cancer cells were more sensitive to growth inhibition by MYC siRNA than HER2 negative cells. The cell cycle arrest induced by MYC knockdown was accompanied by a decrease in cyclin E2 and cyclin A expression and cyclin-dependent kinase 2 (CDK2) activity, suggesting that MYC regulation of CDK2 activity plays a pivotal role in proliferation of MYC-dependent breast cancer cells. MYC-dependent synthetic lethal strategy represents a novel approach to targeting MYC in cancer. Inactivation of CDK2 or CDK1 has been suggested to be synthetic lethal to MYC activation in certain cancer types. We demonstrated that the proliferation of MYC siRNA-sensitive breast cancer cells was significantly reduced by inhibition of CDK1 but not CDK2. Overall, these studies suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer is warranted.