title: Estrogen receptor alpha (ESR1)-signaling regulates the expression of the taxane-response biomarker PRP4K.
abstract: 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. We demonstrated that PRP4K is 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. Breast cancer treatments are chosen based on hormone and growth factor receptor status, with HER2 (ERBB2) positive breast cancer patients receiving anti-HER2 agents and taxanes and estrogen receptor alpha (ESR1) positive (ER+) breast cancer patients receiving anti-estrogen therapies such as tamoxifen. Here we demonstrate 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. Estrogen acts through ESR1 to regulate PRP4K expression, as over-expression of ESR1 in the ER-negative MDA-MB-231 breast cancer cell line increased the expression of this kinase, and knock-down of ESR1 in ER+ T47D breast cancer cells reduced PRP4K levels. Furthermore, treatment with 4-hydroxytamoxifen (4-OHT) resulted in a dose-dependent decrease in PRP4K protein expression in MCF7 cells. Consistent with our previous studies identifying PRP4K as a taxane-response biomarker, reduced PRP4K expression in 4-OHT-treated cells correlated with reduced sensitivity to paclitaxel. Thus, PRP4K is novel estrogen regulated kinase, and its levels can be reduced by 4-OHT in ER+ breast cancer cells altering their response to taxanes.
authors.affiliation: Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Lahsaee
authors.affiliation: Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Dale P
authors.initials: DP
authors.lastname: Corkery
authors.affiliation: Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Livia E
authors.initials: LE
authors.lastname: Anthes
authors.affiliation: Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Alice
authors.initials: A
authors.lastname: Holly
authors.affiliation: Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address: dellaire@dal.ca.
authors.forename: Graham
authors.initials: G
authors.lastname: Dellaire
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D001952:Bridged-Ring Compounds; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; D043823:Taxoids; D013629:Tamoxifen; C080625:taxane; C016601:afimoxifene; C489984:PRPF4B protein, human; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel
keywords: Estrogen; PRP4 kinase; PRPF4B; Tamoxifen; Taxanes