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ESTROGEN RECEPTOR ALPHA SIGNALLING REGULATES THE EXPRESSION OF THE TAXANE-RESPONSE BIOMARKER PRP4K
The hormone estrogen, when bound to its receptor (ER) triggers a cascade of signalling events that result in the proliferation of normal mammary glands. This hormone can also regulate gene expression at the transcriptional level by activating ER-dependent genes and post-transcriptionally by modulating the expression of microRNAs (miRNAs) that alter mRNA stability and translation. The pre-mRNA splicing factor 4 kinase PRP4K (PRPF4B), is an essential kinase that is a component of the U5 snRNP and functions in spliceosome assembly. In this study I demonstrated that PRP4K is expressed in the normal mammary duct epithelial cells of the mouse, and that estrogen induces PRP4K gene and protein expression in ER+ human MCF7 breast cancer cells. Furthermore, I found that this hormonal regulation is via the estrogen receptor alpha, encoded by the ESR1 gene. Thus by modulating levels of PRP4K, estrogen may affect pre-mRNA splicing in tissues expressing ESR1. As a first step towards the characterization of this novel mode of pre-mRNA splicing regulation, I sought to determine the mechanisms behind the hormonal regulation of PRP4K. Although my promoter studies indicated that estrogen does not regulate PRP4K directly at the transcriptional level, I identified several putative binding sites for miRNAs in the 3ʹ-UTR of PRP4K. Several of these miRNAs, including miR-21, are estrogen regulated and/or deregulated in breast cancer. Using ER+ MCF7 breast cancer cells and a dual luciferase reporter system, I have demonstrated that the 3ʹ-UTR of PRP4K can indeed regulate luciferase gene expression and that miR-21 over expression modulates this regulation. PRP4K has been recently shown as a novel biological marker for taxane response in ovarian cancer patients and reduced levels of PRP4K correlate with intrinsic and acquired taxane resistance in both breast and ovarian cancer. Here, I have demonstrated that treatment with tamoxifen, an inhibitor of estrogen signalling, can decrease PRP4K levels in MCF7 breast cancer cells reducing cell sensitivity to the taxane paclitaxel. Thus, this study suggests that PRP4K is novel estrogen regulated kinase, whose expression can be inhibited by tamoxifen in ER+ breast cancer cells which in turn impact cell response to taxanes. These data raise the possibility that by treating ER+ breast cancer patients with anti-estrogen therapies such as tamoxifen, we may inadvertently alter the response of cancer cells to taxane therapy