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    Awarded Grants
    The Role of CKS Proteins in Cell Cycle Control and Breast Cancer

    Scientific Abstract:
    The role of Cks proteins in cell cycle control and breast cancer The two highly homologous orthologs CKS1 and CKS2 are frequently overexpressed in breast cancers and upregulation of CKS1 and CKS2 transcription has been shown to correlate with poor prognosis. Cks proteins are evolutionarily conserved and they are essential for cell cycle propagation in yeast and Xenopus extracts. Mice nullizygous for CKS1 or CKS2 are viable, but deletion of both copies leads to embryonic lethality, indicating that the two genes have redundant, so far unknown functions in mammals. The goal of the proposed work is to determine the redundant function of CKS1 and CKS2 in human and mouse and investigate how increased CKS expression might contribute to breast cancer. To determine the common function of CKS1 and CKS2 in human cells, the expression of both genes will be silenced by viral vector based siRNA expression in immortalized primary human breast epithelial cells and effects on cell morphology, growth speed, and cell cycle phase distribution will be measured. To determine potential downstream targets of CKS, global gene expression will be monitored after silencing of CKS1 and CKS2. The role of Cks in embryonic development will be studied by dissecting embryos at several developmental stages from crosses between CKS1-/- CKS2+/- female and male mice to determine when and why the CKS1-/- CKS2-/- embryos die. To study the correlation between CKS overexpression and breast cancer in more detail, Cks1 and Cks2 protein concentrations will be measured in human primary breast tumors and breast tumor cell lines and the level of protein expression will be correlated with CKS transcription, tumor stage and cell growth. Finally, we will test if ectopic overexpression of CKS1 and CKS2 in breast tumor cell lines is able to increase growth speed in cell culture and in a nude mouse tumor growth model and if the downregulation of the CKS genes has the inverse effect. This study will contribute to understanding the molecular mechanisms leading to breast cancer and will show if targeting the CKS proteins might be a novel approach for treatment.

    Lay Abstract:
    The role of Cks proteins in cell cycle control and breast cancer Breast cancer is caused by genetic alterations that result in uncontrolled cell growth and spreading. Development of breast cancer is accompanied by changes in the cellular gene expression program and up- or downregulation of various genes have been shown to contribute to tumor progression and malignancy. Among the frequently overexpressed genes in breast cancers are the two highly similar genes CKS1 and CKS2 and their upregulation has been shown to correlate with poor prognosis. The goal of the proposed project is to study the common function of the two CKS genes in human and mouse cells and to determine how their upregulation might contribute to breast cancer. Several approaches will be taken to shed light on these questions. We will investigate how increased CKS gene expression translates to protein level in a collection of breast tumor samples, how artificial up- and downregulation of CKS gene expression affects growth in normal and tumorigenic cell lines derived from breast tissues, which other genes are affected by CKS deregulation and what the common essential function of Cks proteins is during mouse embryonic development. This study will contribute to understanding the molecular mechanisms leading to breast cancer and will show if targeting the CKS proteins might be a novel approach for treatment.