The role of FOXM1 and co-factors in breast cancer – endoplasmic reticulum stress, epigenetics, endocrine therapy and chemotherapy
File(s)
Author(s)
Yong, Jay Sze
Type
Thesis
Abstract
Breast cancer is an umbrella term for heterogeneous diseases that originated from
breast tissues. To date, five main treatment strategies are available for breast cancer
treatment – comprising of surgery, radiotherapy, chemotherapy, hormone therapy,
and biological therapy – and these treatments are not categorically exclusive but are
used in combinations. The treatment arrangement is also dependent on the type, size,
location, and stage of cancer. Nevertheless, the interpretation and complete removal
of the disease based on sequencing results remain a challenge. In order to better
tackle the disease, different classifiers have been established to categorise breast
cancer cases into buckets with their own distinct features. Particularly, molecular
subtyping separates breast cancer cases based on the presence of specific markers
such as ESR1, PR, HER2, and Ki-67 with diverse prognostic outcomes and treatment
responses in patients. FOX proteins belong to a transcription factor superfamily that
drives not only important molecular mechanisms in normal cells, but the aberrant
regulation of these members leads to oncogenic outcomes and cancer progression.
Particularly, FOXM1 is an oncogene that is associated with the hallmarks of cancer. It
has been shown that FOXM1 cistrome predicts breast cancer metastatic outcomes
better than FOXM1 expression levels. Therefore, clarity about FOXM1 cistrome and
interactome needs to be prioritised to improve breast cancer treatment and reduce
treatment resistance. In this dissertation, I built on existing knowledge of the role of
FOXM1 in breast cancer cell lines by providing new preliminary insights that pave new
roads for future studies in hormonal and chemotherapeutic response, unfolded protein
response, and epigenetic mechanism. FOXM1 inhibitors are attractive agents to
constitute combinatorial treatment with fulvestrant for constitutively activate ESR1-
positive breast cancer with lower toxicity to cells. Additionally, FOXM1 serves a role in
unfolded protein response in breast cancer cells by a potential axis with endoplasmic
reticulum stress effector, DDIT3. Lastly, FOXM1 differentially interacts with DNA
methyltransferases – specific interaction of FOXM1 and DNMT3B was detected in
MCF-7 and MCF7-EpiR cell lines. Collectively, this study extended our understandings
of the molecular diversity of FOXM1 and its cofactors in breast cancer cell lines and
may serve as a stepping stone to identify prognostic markers and treatment targets in
breast cancer.
breast tissues. To date, five main treatment strategies are available for breast cancer
treatment – comprising of surgery, radiotherapy, chemotherapy, hormone therapy,
and biological therapy – and these treatments are not categorically exclusive but are
used in combinations. The treatment arrangement is also dependent on the type, size,
location, and stage of cancer. Nevertheless, the interpretation and complete removal
of the disease based on sequencing results remain a challenge. In order to better
tackle the disease, different classifiers have been established to categorise breast
cancer cases into buckets with their own distinct features. Particularly, molecular
subtyping separates breast cancer cases based on the presence of specific markers
such as ESR1, PR, HER2, and Ki-67 with diverse prognostic outcomes and treatment
responses in patients. FOX proteins belong to a transcription factor superfamily that
drives not only important molecular mechanisms in normal cells, but the aberrant
regulation of these members leads to oncogenic outcomes and cancer progression.
Particularly, FOXM1 is an oncogene that is associated with the hallmarks of cancer. It
has been shown that FOXM1 cistrome predicts breast cancer metastatic outcomes
better than FOXM1 expression levels. Therefore, clarity about FOXM1 cistrome and
interactome needs to be prioritised to improve breast cancer treatment and reduce
treatment resistance. In this dissertation, I built on existing knowledge of the role of
FOXM1 in breast cancer cell lines by providing new preliminary insights that pave new
roads for future studies in hormonal and chemotherapeutic response, unfolded protein
response, and epigenetic mechanism. FOXM1 inhibitors are attractive agents to
constitute combinatorial treatment with fulvestrant for constitutively activate ESR1-
positive breast cancer with lower toxicity to cells. Additionally, FOXM1 serves a role in
unfolded protein response in breast cancer cells by a potential axis with endoplasmic
reticulum stress effector, DDIT3. Lastly, FOXM1 differentially interacts with DNA
methyltransferases – specific interaction of FOXM1 and DNMT3B was detected in
MCF-7 and MCF7-EpiR cell lines. Collectively, this study extended our understandings
of the molecular diversity of FOXM1 and its cofactors in breast cancer cell lines and
may serve as a stepping stone to identify prognostic markers and treatment targets in
breast cancer.
Version
Open Access
Date Issued
2021-05
Date Awarded
2021-10
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Yague, Ernesto
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)