title: Identification of fibroblast growth factor-8b target genes associated with early and late cell cycle events in breast cancer cells.
abstract: Fibroblast growth factor-8 (FGF-8) is implicated in the development and progression of breast cancer and its levels are frequently elevated in breast tumors. The mechanisms driving FGF-8-mediated tumorigenesis are not well understood. Herein we aimed to identify target genes associated with FGF-8b-mediated breast cancer cell proliferation by carrying out a cDNA microarray analysis of genes expressed in estrogen receptor negative S115 breast cancer cells treated with FGF-8b for various time periods in comparison with those expressed in non-treated cells. Gene and protein expression was validated for selected genes by qPCR and western blotting respectively. Furthermore, using TRANSBIG data, the expression of human orthologs of FGF-8-regulated genes was correlated to the Nottingham prognostic index and estrogen receptor status. The analysis revealed a number of significantly up- and down-regulated genes in response to FGF-8b at all treatment times. The most differentially expressed genes were genes related to cell cycle regulation, mitosis, cancer, and cell death. Several key regulators of early cell cycle progression such as Btg2 and cyclin D1, as well as regulators of mitosis, including cyclin B, Plk1, survivin, and aurora kinase A, were identified as novel targets for FGF-8b, some of which were additionally shown to correlate with prognosis and ER status in human breast cancer. The results suggest that in stimulation of proliferation FGF-8b not only promotes cell cycle progression through the G1 restriction point but also regulates key proteins involved in chromosomal segregation during mitosis and cytokinesis of breast cancer cells.
authors.affiliation: Department of Laboratory Medicine, Tumor Biology, Lund University, Sweden. Emeli.Nilsson@med.lu.se
authors.forename: E M
authors.initials: EM
authors.lastname: Nilsson
authors.forename: L J S
authors.initials: LJ
authors.lastname: Brokken
authors.forename: E
authors.initials: E
authors.lastname: Narvi
authors.forename: M J
authors.initials: MJ
authors.lastname: Kallio
authors.forename: P L
authors.initials: PL
authors.lastname: Härkönen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008938:Mitosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000096:biosynthesis; D015398:Signal Transduction; D000077022:Survivin; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D064096:Aurora Kinase A; D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D019926:Cyclin B; D019938:Cyclin D1; D051524:Fibroblast Growth Factor 8; D017874:Immediate-Early Proteins; D051034:Inhibitor of Apoptosis Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D000077022:Survivin; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; C107489:BIRC5 protein, human; C070114:BTG2 protein, human; C576917:AURKA protein, human; C576918:Aurka protein, mouse