A new pathway in the induction of breast cancer

Watkins, Rachel Jane (2010). A new pathway in the induction of breast cancer. University of Birmingham. Ph.D.

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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:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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