Cytidine Deaminases are Regulators of Estrogen Receptor Activity in Breast Cancer Cells
Author(s)
Periyasamy, Manikandan
Type
Thesis
Abstract
Breast cancer is the most common cancer worldwide, with 1.38 million women
diagnosed with the disease each year. Estrogens play a critical role in the development
and progression of breast cancer, their action being mediated by the estrogen
receptors (ER), ERα and ERß, which are the members of the nuclear receptor
superfamily of transcription factors. This understanding has led to the development of
endocrine therapies aimed at inhibiting ER action by competitive binding to the ER
(anti-estrogens), or using inhibitors of estrogen biosynthesis (aromatase inhibitors).
Determining the mechanisms by which ER regulate gene expression will aid our
understanding of the role of ER in breast cancer progression, response and resistance
to endocrine therapies. Upon binding estrogen, ER drives the expression of estrogen
responsive genes through the orderly recruitment of co-regulators that act by
remodelling and modifying chromatin, ultimately promoting RNA polymerase II
recruitment and transcription initiation. Previous work from our laboratory has shown
that the APOBEC3B cytosine deaminase acts as an ERα transcriptional coactivator in
reporter gene assays. Here, I have developed these initial observations and
demonstrate that APOBEC3B is important for the regulation of estrogen responsive
genes and breast cancer cell growth. I show that APOBEC3B is recruited to the
promoters of estrogen-responsive genes and interacts with ERα. Studies carried out to
identify the molecular mechanisms by which APOBEC3B regulates the expression of
estrogen-responsive genes included its potential role in DNA demethylation and
identified a role for APOBEC3B in DNA strand break formation at the promoter of
the estrogen regulated pS2 gene. Together, these studies identify APOBEC3B as an
important new coregulator of ERα that is required for the regulation of gene
expression by estrogen in breast cancer cells.
diagnosed with the disease each year. Estrogens play a critical role in the development
and progression of breast cancer, their action being mediated by the estrogen
receptors (ER), ERα and ERß, which are the members of the nuclear receptor
superfamily of transcription factors. This understanding has led to the development of
endocrine therapies aimed at inhibiting ER action by competitive binding to the ER
(anti-estrogens), or using inhibitors of estrogen biosynthesis (aromatase inhibitors).
Determining the mechanisms by which ER regulate gene expression will aid our
understanding of the role of ER in breast cancer progression, response and resistance
to endocrine therapies. Upon binding estrogen, ER drives the expression of estrogen
responsive genes through the orderly recruitment of co-regulators that act by
remodelling and modifying chromatin, ultimately promoting RNA polymerase II
recruitment and transcription initiation. Previous work from our laboratory has shown
that the APOBEC3B cytosine deaminase acts as an ERα transcriptional coactivator in
reporter gene assays. Here, I have developed these initial observations and
demonstrate that APOBEC3B is important for the regulation of estrogen responsive
genes and breast cancer cell growth. I show that APOBEC3B is recruited to the
promoters of estrogen-responsive genes and interacts with ERα. Studies carried out to
identify the molecular mechanisms by which APOBEC3B regulates the expression of
estrogen-responsive genes included its potential role in DNA demethylation and
identified a role for APOBEC3B in DNA strand break formation at the promoter of
the estrogen regulated pS2 gene. Together, these studies identify APOBEC3B as an
important new coregulator of ERα that is required for the regulation of gene
expression by estrogen in breast cancer cells.
Date Issued
2011
Date Awarded
2012-01
Advisor
Buluwela, Laki
Ali, Simak
Creator
Periyasamy, Manikandan
Publisher Department
Medicine: Department of Surgery and Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)