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A new pathway in the induction of breast cancer

Watkins, Rachel Jane (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

The association of breast cancer risk with menarche, menopause and first full-term pregnancy, as well as oral contraceptive use and hormone replacement therapy, suggests a role for hormones in the development of carcinomas. Pituitary tumor transforming gene Binding Factor (PBF) is a relatively uncharacterized gene implicated in endocrine neoplasia. Given the presence of putative oestrogen response elements (ERE) in its promoter, we assessed PBF regulation by oestrogen. PBF mRNA and protein expression were induced by both diethylstilbestrol and 17ß-estradiol in ER!-positive MCF-7 cells. Close analysis of the PBF promoter showed that the region -399 to -291 relative to the translational start site contains variable repeats of an 18bp sequence housing a putative ERE half-site (gcccctcGGTCAcgcctc). Sequencing the PBF promoter from 122 normal subjects revealed that individuals may be homozygous or heterozygous for between 1 and 6 repeats of the ERE. PBF expression was low or absent in normal breast tissue, but highly expressed in breast tumours. Individuals with greater numbers of repeats demonstrated higher PBF mRNA expression, and protein expression positively correlated with ER\(\alpha\) status. Cell invasion assays revealed that PBF induces invasion through Matrigel, an action that could be abrogated both by siRNA treatment and specific mutation. Further, PBF is a secreted protein, and loss of secretion prevents PBF inducing cell invasion. Given that PBF is a potent transforming gene, these data suggest that oestrogen treatment in post-menopausal women may up-regulate PBF expression, leading to PBF secretion and increased cell invasion. Further, the number of ERE half sites in the PBF promoter may significantly alter the response to oestrogen treatment in individual subjects.

Type of Work:Ph.D. thesis.
Supervisor(s):McCabe, Chris and Boelaert, Kristien and Franklyn, Jane A.
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Department of Clinical and Experimental Medicine
Subjects:R Medicine (General)
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:765
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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