Page 1 |
Save page Remove page | Previous | 1 of 152 | Next |
|
small (250x250 max)
medium (500x500 max)
large ( > 500x500)
Full Resolution
All (PDF)
|
This page
All
Subset |
MECHANISMS OF OVARIAN CANCER PREDISPOSITION IN BRCA1 MUTATION
CARRIERS
by
Hao Hong
____________________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
August 2008
Copyright 2008 Hao Hong
Object Description
| Title | Mechanisms of ovarian cancer predisposition in BRCA1 mutation carriers |
| Author | Hong, Hao |
| Author email | haohong@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pathobiology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-05-30 |
| Date submitted | 2008 |
| Restricted until | Restricted until 1 July 2010. |
| Date published | 2010-07-01 |
| Advisor (committee chair) | Dubeau, Louis |
| Advisor (committee member) |
Roy-Burman, Pradip Maxson, Robert E. Chuong, Cheng-Ming |
| Abstract | The exact mechanism by which Breast Cancer Susceptibility Gene1 (BRCA1) mutations predispose to breast and ovarian cancer remains poorly understood.; Our laboratory developed a mouse model for epithelial ovarian cystadenoma based on inactivation of Brca1 specifically in ovarian granulosa cells which play a critical role in regulating menstrual cycle and a subset of cells in pituitary via Cre-loxP technology.; My project was to study the possible mechanisms of ovarian tumors development in this mouse model. I characterized dynamics of ovulatory cycles of these mice in a large scale and over a long period time. Mutant mice showed statistically significant increase in the length of proestrus phase, increases in the length ratio of proestrus/metestrus and diestrus combined, and increases in the length ratio of proestrus/metestrus. Moreover, these estrus cycle abnormalities were associated with tumor predisposition.; These results suggest mutant mice have a relative increase in estrogen growth stimulation unopposed by progesterone. Given the well known influence of the menstrual cycle and estrogen as important risk factors for ovarian cancer and progesterone as a protective factor, my studies raise the possibility that predisposition to ovarian and breast cancers in individuals bearing germline BRCA1 mutations may be due, at least in part, to menstrual cycle changes driven by these mutations.; My studies also strongly supported our hypothesis that BRCA1/Brca1 controls tumor development in a cell non-autonomous manner as opposed to acting as a classical tumor suppressor gene by indirectly modulating the estrus cycle. This novel role for Brca1 suggests a new possible mechanism for tumor tissue specificity in BRCA1 mutations carriers.; In order to distinguish between any effects of Brca1 inactivation in the pituitary versus granulosa cells, I performed ovarian transplantation. My studies showed the estrus cycle changes in the mutant mice were driven by granulosa cells as opposed to pituitary cells.; Lastly I found that germline transmission of a mutant Brca1 allele had taken place in some of the mutant mice despite the tissue specificity of the promoter we used to drive Cre. Such germline rearrangement occurred through parental transmission of Cre recombinase but the transmission frequency is lower via female transmission. |
| Keyword | ovarian cancer; BRCA1 |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1309 |
| Rights | Hong, Hao |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Hong-20080701 |
| Archival file | uscthesesreloadpub_Volume26/etd-Hong-20080701.pdf |
Description
| Title | Page 1 |
| Full text | MECHANISMS OF OVARIAN CANCER PREDISPOSITION IN BRCA1 MUTATION CARRIERS by Hao Hong ____________________________________________________________ A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PATHOBIOLOGY) August 2008 Copyright 2008 Hao Hong |
Comments
Post a Comment for Page 1
