UNIVERSITY OF CALGARY Regulation of Breast Cancer Cell Proliferation by APRIL by

UNIVERSITY OF CALGARY
Regulation of Breast Cancer Cell Proliferation by APRIL
by
Wejdan Matook
A THESIS
SUBMITTED TO THE FACULTY OF GRADUATE STUDIES
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE
DAGREE OF MASTER OF SCIENCE
GRADUATE PROGRAM IN MEDICAL SCIENCE
CALGARY, ALBERTA
June, 2016
© Wejdan Matook 2016

Abstract
Breast cancer is the most common cause of death from cancer among women. “A proliferation-
inducing ligand” (APRIL) is seen in the stroma of approximately 38% of breast cancer patients.
APRIL is a tumor necrosis factor superfamily member that is implicated in lymphoid cell survival,
proliferation and apoptosis. APRIL studies initially focused on lymphoid cells as known APRIL
receptors are exclusive to these cells. However, I found that APRIL promotes breast cancer cell
proliferation, and an APRIL-specific blocking peptide inhibits APRIL-induced proliferation.
Therefore, I sought to identify APRIL targets in breast cancer cells. Among those identified,
colony-stimulating factor 2 receptor beta (CSF2RB) is interesting. CSF2RB-APRIL interaction is
direct, and the CSF2RB ligand, CSF2, has 41% amino acid sequence similarity to APRIL.
CSF2RB-linked Akt and STAT3 signaling are activated in APRIL-mediated breast cancer cell
proliferation. Thus, my findings raise the possibility that CSF2RB is a novel APRIL receptor in
non-lymphoid cells.
II

Acknowledgements
I would like to thank both Drs. Ki-Young Lee and Susie Rosales for providing me the opportunity
to conduct a very exciting project for my M.Sc. degree at the University of Calgary. I thank both
Drs. Brockton and Riabowol for their guidance and constructive criticisms that stimulated my
critical thinking. I also thank my external examiner, Dr. Tina Cheng, for her critical input during
my thesis defence, and Dr. Roman Krawetz for serving as the neutral chair for my M.Sc. defence.
I thank my peers in Dr. Lee’s laboratory (Uilst, Sung-Myung, Alex, Guohong, Vincent, Saranya,
Kwon-Jung) for their friendship and for providing a very supporting environment. I thank the
Saudi Arabia’s King Abdullah Scholarship Program and the Ministry of Education for giving me
the opportunity to continue my education in Canada. Finally, I would like to thank my family for
all their support.
III

Dedication
I dedicate this work to my mother, father, siblings and friends who supported, listened, and
encouraged me to continue my studies and complete my M.Sc. degree.
Thank you all for everything
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Table of Contents
Abstract ................................................................................................................................ II
Acknowledgements .............................................................................................................. III
Dedication ............................................................................................................................ IV
Table of Contents .................................................................................................................. V
List of Tables ........................................................................................................................ IX
List of Figures and Illustrations .............................................................................................. X
List of Symbols, Abbreviations and Nomenclature ................................................................ XI
Chapter One: Introduction, Hypothesis and Objective .....................................................................1
1.1 Introduction .................................................................................................................................... 2
1.1.1 Breast cancer .......................................................................................................................................... 2
1.1.1.1 Breast cancer treatment ................................................................................................................. 3
1.1.2 Tumor necrosis factor superfamily (TNFSF) ........................................................................................... 4
1.1.2.1 TNF ligands and receptors .............................................................................................................. 4
1.1.2.2 TNFSF function ................................................................................................................................ 9
1.1.3 “A proliferation-inducing ligand” (APRIL) is a member of the TNFSF of cytokines ................................ 9
1.1.3.1 APRIL gene and protein domains .................................................................................................... 9
1.1.3.2 APRIL receptors ............................................................................................................................ 12
1.1.3.3 APRIL function and signaling ........................................................................................................ 13
1.1.4 PI3K/AKT signaling in cell survival, proliferation and apoptosis. .......................................................... 14
1.1.4.1 PI3K/AKT signaling ........................................................................................................................ 14
1.1.4.2 PI3K/AKT-associated function ...................................................................................................... 16
V