licing kinases, has recently been shown to function as an oncogene in breast cancer.65 A lentiviral shRNA cell viability screen was carried out that targeted 26 genes which the authors found to be commonly overexpressed or amplified in breast tumors or breast cancer cell lines based on SNP array analysis.65 Of the 26 targets, knock-down of CLK2 was identified for its ability to inhibit breast cancer cell growth in vitro, and later confirmed to inhibit tumorigenesis in a mouse xenograft model. However, the knock-down of CLK2 was also shown to promote metastasis and invasion of breast cancer cells in vivo by inducing alternative splice patterns characteristic of the epithelial-to-mesenchymal transition. Specifically, knockdown of CLK2 was shown to regulate the alternative splicing of ENAH, an actin cytoskeletal protein, which contains a small coding exon which is PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19841886 included in the mRNA of epithelial cells, but excluded in mesenchymal cells.65 Loss of CLK2 promoted the exclusion of exon 11a. Thus, CLK2 expression levels could represent an important marker for EMT during breast cancer progression. PRP4K PRP4K, the least studied of the 3 splicing kinases, has recently begun to emerge as an important regulator of therapeutic response. In addition to its role in splicing, PRP4K has been implicated in the regulation of mitosis as expression of a dominant truncated form of PRP4K in S. pombe was shown to induce mitotic aberrations.102 Consequently, mammalian PRP4K was shown to be a regulator of the mitotic spindle assembly checkpoint through its ability to recruit checkpoint proteins MPS1, MAD1 and MAD2 to the kinetochore.103 This finding has important implications for therapeutic response to taxanes, a family of anti-cancer agents that depend on SAC activity for cell killing.104 The taxanes function by binding to and stabilizing mictrotubules, resulting in a disruption of microtubule dynamics. As a cell progresses through mitosis, taxanes inhibit the ability of sister chromatids to properly segregate which triggers activation of the SAC and arrests the cell in prometaphase.105 If the checkpoint cannot be satisfied, its prolonged activation will result in mitotic cell death.106 Not surprisingly, disruption of SAC function has been has been shown to increase cellular resistance to taxanes in a number of different cancer models.107-112 Consistent with these models, we have shown that 
PRP4K functions downstream of the receptor tyrosine kinase HER2 to regulate paclitaxel response in breast and ovarian cancer, presumably by altering SAC activity, and that its expression is decreased in ovarian cancer patients that have relapsed from taxane treatment.113 Importantly, we also demonstrated that, among ovarian cancer patients with low HER2 expressing tumors, PRP4K expression can be used as a predictive marker to identify patients likely to benefit from taxane therapy.113 In addition to promoting resistance to microtubule targeting chemotherapeutics, disruptions in the SAC has been suggested to facilitate tumorigenesis by inducing chromosomal instability, a hallmark of human neoplasia.114,115 Under normal conditions, the SAC becomes activated in response to one or more unattached chromosomes, blocking progression to MedChemExpress XAV-939 anaphase. When checkpoint components are mutated, or expression levels decreased, un-attached chromosomes are unable to activate the SAC and become mis-segregated, leading to increased aneuploidy.116-118 While it is still unclear as to whether or