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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/32954

Title: The Role of Luteal Phase Fallopian Tube Epithelium in High-grade Ovarian Serous Carcinoma
Authors: Tone, Alicia
Advisor: Shaw, Patricia
Brown, Theodore
Department: Laboratory Medicine and Pathobiology
Keywords: ovarian cancer
fallopian tube
serous
glucocorticoid
inflammation
BRCA1
DAB2
progesterone
luteal
gene expression profiling
Issue Date: 5-Sep-2012
Abstract: Studies of prophylactic salpingectomy specimens from BRCA1/2 mutation carriers, at risk for tubal and ovarian high-grade serous carcinoma (SerCa), have consistently revealed occult carcinomas and putative histological cancer precursors in the distal fallopian tube epithelium (FTE), supporting the FTE as the source of SerCa. In this thesis I molecularly characterized and compared non-malignant FTE from mutation carriers (FTEb) and control patients (FTEn) to identify alterations that may predispose to malignant transformation. Gene expression profiling of laser capture microdissected FTEn, FTEb and SerCa indicated that SerCa have similar molecular profiles whether of presumed ovarian or tubal origin, supporting the notion they share a common cell of origin within the FTE. Furthermore, FTEb samples obtained during the post-ovulatory luteal phase showed gene expression profiles closely resembling SerCa samples, suggesting that the luteal phase milieu may contribute to serous carcinogenesis. An initial hypothesis was that FTEb may respond differently to luteal progesterone compared to FTEn, via differential expression of progesterone receptor (PR) isoforms. However, similar relative isoform expression in FTEn and FTEb samples suggested that a luteal phase-associated factor other than progesterone directs gene expression changes in FTEb. The possibility that FTEb respond differently to ovulation-associated inflammatory cytokines that are locally elevated during the luteal phase was next investigated. Importantly, FTEb specimens previously found to cluster with SerCa based on their global gene expression profiles showed evidence of increased nuclear factor-κB (NFκB)-dependent (pro-inflammatory) signalling and diminished glucocorticoid receptor (GR)-dependent (anti-inflammatory) signalling. Furthermore, I demonstrate that disabled homolog 2 (DAB2), an adaptor molecule decreased in SerCa and FTE luteal samples, enhances both GR-mediated transactivation and suppression of NFκB signalling, implicating DAB2 as a crucial determinant of inflammatory signalling and ovarian cancer risk. Altogether, this thesis identifies gene expression changes in FTE from BRCA mutation carriers during the post-ovulatory luteal phase that parallel those detected in SerCa. The data support a proposed novel testable model for predisposing events contributing to SerCa that centres on an altered ability to quickly resolve the pro-inflammatory environment created by the ovulatory event.
URI: http://hdl.handle.net/1807/32954
Appears in Collections:Doctoral

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Tone_Alicia_A_201006_PhD_thesis.pdfThesis Main File2.51 MBAdobe PDF
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Tone_Alicia_A_201006_PhD_Appendix I.pdfAppendix I566.4 kBAdobe PDF
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Tone_Alicia_A_201006_PhD_Appendix II.pdfAppendix II351.37 kBAdobe PDF
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