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dc.contributor.authorHedberg, Carola
dc.date.accessioned2009-08-28T11:03:52Z
dc.date.available2009-08-28T11:03:52Z
dc.date.issued2009-08-28T11:03:52Z
dc.identifier.isbn978-91-628-7825-2
dc.identifier.urihttp://hdl.handle.net/2077/20300
dc.description.abstractEndometrial carcinoma (EC) is the most common form of gynecological malignancy, ranking fourth in incidence among tumors diagnosed in women. As is the case with other complex diseases, detailed analyses of the underlying mechanisms of cancer are difficult, due mainly to the genetic heterogeneity of the human population and differences in the environment and lifestyle of individuals. In this sense, analysis in animal models may serve as a valuable complement. The inbred BDII rat strain is genetically prone to spontaneous hormone-related EC and it has been used as a powerful model to investigate molecular alterations in this tumor type. BDII female rats were crossed with males from two non-susceptible rat strains and tumors were developed in a significant fraction of the progeny. We subjected a subset of BDII rat tumors to detailed analysis based on the molecular data used for the classification of human ECs. Our analysis revealed that this tumor model can be related to higher grade human type I ECs, i.e. a subgroup of ECs that constitutes more than 80% of this tumor type in humans. Earlier work using comparative genome hybridization (CGH) revealed that rat chromosome 10 (RNO10) was frequently involved in cytogenetic aberrations in BDII rat tumors. To identify the potential target region(s)/gene(s) for these changes, we subjected a panel of rat ECs to allelic imbalance (AI) analysis. Four distinct regions of recurrent AI were identified. By deriving evolutionary tree models based on AI data, we demonstrated that one of these AI regions (located adjacent to Tp53) was close to the root in the derived onco-tree models, indicating that this segment might harbor early important events. In combined FISH, chromosome paint, gene expression and gene sequencing analyses, we found that, instead of Tp53, the main selection target was a region close and distal to Tp53. We developed a detailed deletion map of this area and substantially narrowed down the size of the candidate region. We then subjected all 19 genes located within this segment to qPCR analysis, followed by statistical analysis of the results, and thus identified the Hic1, Skip and Myo1c genes as potential target(s). By subjecting these genes to DNA sequencing, analysis of protein expression and of epigenetic silencing, we ruled out Hic1 and confirmed Skip and Myo1c as the candidates. Interestingly, it appears that Skip and Myo1c perform overlapping roles in PI 3-kinase/Akt signaling, which is known to have implications for the survival and growth of cancer cells. In conclusion, starting from cytogenetic findings and applying a candidate gene approach, we introduced two attractive candidate genes within the independent region of tumor suppressor activity distal to Tp53.en
dc.language.isoengen
dc.relation.haspartI: Samuelson Emma, Hedberg Carola, Nilsson Staffan, and Behboudi Afrouz. Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats. Endocrine-Related Cancer: 2009; 16: 99-111. ::PMID::19075038en
dc.relation.haspartII: Nordlander Carola, Behboudi Afrouz, Levan Göran, Klinga-Levan Karin. 2005. Allelic imbalance on chromosome 10 in rat endometrial adenocarcinomas. Cancer Genetics and Cytogenetics: 2005; 156: 158-166. ::doi::10.1016/j.cancergencyto.2004.05.001en
dc.relation.haspartIII: Chen Lei, Nordlander Carola, Behboudi Afrouz, Olsson Björn, and Klinga-Levan Karin. Deriving evolutionary tree models of the oncogenesis of endometrial adenocarcinomas. International Journal of Cancer: 2006; 120: 292-296. ::doi::10.1002/ijc.22165en
dc.relation.haspartIV: Nordlander Carola, Karlsson Sandra, Karlsson Åsa, Sjöling Åsa, Winnes Marta, Klinga-Levan Karin, and Behboudi Afrouz. Analysis of chromosome 10 aberrations in rat endometrial cancer – evidence for a tumor suppressor locus distal to Tp53. International Journal of Cancer: 2007; 120: 1472-1481. ::doi::10.1002/ijc.22533en
dc.relation.haspartV: Hedberg Carola, Garcia Dios Diego, Linder Anna, Samuelson Emma, Ejeskär Katarina, Abel Frida, Karlsson Sandra, Nilsson Staffan, and Behboudi Afrouz. Analysis of the independent tumor suppressor loci telomeric to Tp53 suggests Skip and Myo1c as novel tumor suppressor gene candidates in experimental endometrial carcinoma. Unpublished manuscripten
dc.subjectcanceren
dc.subjectendometrial canceren
dc.subjecttumor suppressor geneen
dc.subjectrat modelsen
dc.subjectSkipen
dc.subjectMyo1cen
dc.titleNovel Tumor Suppressor Gene Candidates in Experimental Endometrial Carcinoma - From Cytogenetic to Molecular Analysisen
dc.typeText
dc.type.svepDoctoral thesiseng
dc.gup.mailCarola.Hedberg@gu.seen
dc.type.degreeDoctor of Philosophyen
dc.gup.originGöteborgs universitet. Naturvetenskapliga fakultetenen
dc.gup.departmentDepartment of Cell and Molecular Biology ; Institutionen för cell- och molekylärbiologien
dc.gup.defenceplace9.00 Arvid Carlsson, Medicinaregatan 3en
dc.gup.defencedate2009-09-24
dc.gup.dissdb-fakultetMNF


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