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«Mollecula and functi ar ional a analys of tumor sis r hete erogen neity in brea can x ast ncer xenogr mo raft odels Nirm Škrb ma bo Depart tment of ...»

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Mollecula and functi

ar ional a

analys of tumor

sis r

hete

erogen

neity in brea can x

ast ncer xenogr mo

raft odels

Nirm Škrb

ma bo

Depart tment of C

Cancer Geenetics

Institu for Can Resea

ute ncer arch

The Norwegian Radium H Hospital

Divisio of Can Medic

on ncer cine, Surgery and Tr

ransplanta

ation

Oslo UUniversity Hospital

Faculty of Medi

y icine

Univerrsity of Os

slo

© Nirma Škrbo, 2016

Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8333-140-0 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission.

Cover: Hanne Baadsgaard Utigard Printed in Norway: 07 Media AS – www.07.no Acknowledgements The work presented in this thesis was carried out at the Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, the Norwegian Radium Hospital during the period 2011-2015. The financial support from Helse Sør-Øst has been greatly appreciated.

I would like to express my sincere gratitude to Therese Sørlie, my main supervisor, for including me into her research group and giving me the opportunity to begin working on my PhD thesis.

Dear Therese, thank you for always being positive, supportive and believing in my ability to accomplish this goal. I appreciate your invaluable guidance and feedback you gave me throughout this academic journey. Your enthusiasm for the research has been a great inspiration to my work. I am especially grateful for the encouragement extended which helped me develop as a scientist. You have always been opened for my interests and suggestions. Your integrity and positive and calm spirit have been great support, and I am truly grateful for that.

I am very thankful to my co-supervisor Kristin Andersen, who extended her daily assistance and tremendous supervision. Dear Kristin, it has been a joy working with you during all these years.

You have been my mentor in so many ways, and I am deeply grateful for everything you have taught me. Your enormous patience, compassion and the emotional support meant a world to me.

Thank you for always encouraging my ideas, acknowledging my opinion and for having confidence in me. Above all, I want to thank you for treating me as your equal. Your positive spirit and enthusiasm shown for my achievements have contributed greatly to my motivation during this journey.

Furthermore, I would like to sincerely thank Professor Anne-Lise Børresen-Dale, Head of the Department of Cancer Genetics for providing an excellent research environment. By being part of her Department I was fortunate enough to experience her enthusiasm, dedication to cancer research and her generous sharing of knowledge with all of us at the Department.

The work presented in this thesis was performed in collaboration with the Department of Tumor Biology. I would like to express my gratitude to Professor Gunhild M. Mælandsmo, Head of the Department of Tumor Biology, for welcoming me into her group. Dear Gunhild, thank you for giving me my first job at Radiumhospitalet. I wouldn’t be here without your help and continuous support over the years, and I am deeply grateful for that.

The collaboration with all my co-authors is greatly appreciated. In particular, I would like to sincerely thank Alexander, Ufuk, Linn, Siver, Paolo, Maria, Silje, Peter and Olav for invaluable discussions and their important contribution to the papers included in this thesis. I would also like to acknowledge the significant assistance from Idun and Kirsti at the Flow Cytometry Core Facility.

To my colleagues at the Departments of Cancer Genetics and Tumor Biology, thank you all for providing such a stimulating and enjoyable environment. Many of you have been important sources of inspiration, support and help. I am particularly thankful to Lina Prasmickaite who introduced me to cell culturing techniques and flow cytometry, which proved to be so useful in later years when I started working on my thesis. Dear Lina, thank you for always being interested in my research and for valuable scientific discussions and inputs. I further want to thank Ellen Tenstad for stimulating team-work on our review article and for the graphical illustrations in the third paper of this thesis. Dear Ellen, I admire your sense for details - working with you has been inspiring and enlightening and I am grateful for everything I learned from you. Dear Kotryna, thank you for being a wonderful office mate, for your care and support when I needed it the most.

To Therese’s group, thank you all for the interesting and inspiring scientific discussions, but also for the great humor and good times at our meetings.

Simen, thank you for all the good discussions and for always showing interest in my projects. I admire your bright and sharp approach to science and I am extremely thankful for all your feedback and scientific inputs. Especially, I thank you for your willingness to read the first drafts of this thesis.

Siri and Lina C, I have been fortunate to have you as my colleagues, but most important as my dear friends. Your emotional support and your invaluable experience that you unselfishly shared with me made this much easier and more fun.





I am fortunate to have so many good friends - I thank you all for your encouragement, for showing interest in what I do, but most important for the great times we shared.

Finally, very special thanks to my family for giving me the life that I appreciate so much. Mama, Tata and Đana, thank you for always being there for me, for your unconditional love and support in everything I do. Vi ste moje sve na svijetu i bez vas ovo nikada ne bih postigla. Volim vas puno! Bako, hvala ti za svu ljubav, pažnju i za sve što si me naučila. To Đana, Kjetil and my lovely nieces Iris and Sara, thank you for all the fun during some hard times that was keeping me sane. I am looking forward to my future with you.

Oslo, January 2016 Contents Aims

List of papers

Abbreviations

Introduction

Anatomy and histology of the normal breast

Breast cancer epidemiology

Breast cancer initiation and progression

Breast cancer taxonomy

Histopathological classification

Prognostic and predictive biomarkers

Histological grade

Stage; TNM classification

Cellular receptor classification

Ki-67

Molecular classification; gene-expression signatures as classifiers

Breast cancer treatment

Surgery and radiation therapy

Systemic treatments

Causes and consequences of intratumor heterogeneity

Sources of heterogeneity within cancer

Impact of intratumor heterogeneity on therapy response

Cancer cell metabolism and metabolic reprogramming

Aerobic glycolysis; the Warburg effect

Metabolic heterogeneity in cancer

Lipids and cholines in breast cancer

Material and methods

Material

Clinical breast cancer samples

Breast cancer patient derived xenograft models

Mice strains used in this study

Technology

mRNA expression microarrays

SNP-arrays

High Resolution Magic Angle Spinning Magnetic Resonance Spectroscopy

Mass spectrometry

Flow cytometry

Summary of results

Paper I

Interplay of choline metabolites and genes in patient-derived breast cancer xenografts

Paper II

Differential in vivo tumorigenicity of distinct subpopulations from a luminal-like breast cancer xenograft

Paper III

Protein expression analysis reveals mechanisms for estrogen-independence in tumor cell subpopulations of a luminal-like breast cancer xenograft

Discussion

Using PDX as a model for human breast cancer

Relevance of intratumor phenotypic heterogeneity

Markers for studying phenotypic and functional heterogeneity

Regulation of metabolism in breast cancer

Concluding remarks and future perspectives

References

Aims The overall aim of this project was to identify new criteria for better patient stratification and to increase the knowledge on how cancer cells evade cancer therapy.

The specific aims for the studies in this thesis were to:

- Evaluate whether patient derived breast cancer xenografts are relevant models for studying molecular characteristic of breast tumors.

- Investigate intertumor heterogeneity with a particular focus on breast cancer subtypespecific regulation of choline metabolism.

- Identify different cancer cell subpopulations in a luminal-like breast tumor and assess their tumor initiating potential and their molecular differences.

- Examine whether cancer cell subpopulations respond differently to anti-estrogen therapy and assess molecular changes that occur in response to treatment.

List of papers Paper I Interplay of choline metabolites and genes in patient-derived breast cancer xenografts Maria T Grinde, Nirma Skrbo, Siver A Moestue, Einar A Rødland, Eldrid Borgan, Alexandr Kristian, Beathe Sitter, Tone F Bathen, Anne-Lise Børresen-Dale, Gunhild M Mælandsmo, Olav Engebraaten, Therese Sørlie, Elisabetta Marangoni and Ingrid S Gribbestad Breast Cancer Research 2014, 16:R5. doi: 10.1186/bcr3597 Paper II Differential in vivo tumorigenicity of distinct subpopulations from a luminal-like breast cancer xenograft Nirma Skrbo, Geir-Olav Hjortland, Alexandr Kristian, Ruth Holm, Silje Nord, Lina Prasmickaite, Olav Engebraaten, Gunhild M. Mælandsmo, Therese Sørlie and Kristin Andersen PLoS One 2014, 9(11):e113278. doi: 10.1371/journal.pone.0113278 Paper III Protein expression analysis reveals mechanisms for estrogen-independence in tumor cell subpopulations of a luminal-like breast cancer xenograft Nirma Skrbo, Ufuk Kirik, Alexandr Kristian, Paolo Cifani, Linn Antberg, Siver A. Moestue, Olav Engebraaten, Gunhild M. Mælandsmo, Kristin Andersen, Peter James and Therese Sørlie Manuscript Abbreviations AML Acute myeloid leukemia ATP Adenosine triphosphate BAF B-allele frequency BC Breast cancer BCI Breast cancer index CGH Comparative genomic hybridization CID Collision-induced dissociation CNA Copy number alteration CSC Cancer stem cells CTP Cytidine triphosphate DCIS Ductal carcinoma in situ DMFS Distant metastasis free survival DNA Deoxyribonucleic acid ECM Extracellular matrix EMT Epithelial mesenchymal transition ER Estrogen receptor alpha ESI Electrospray ionization FACS Fluorescence activated cell sorting FDG Fluorodeoxyglucose FFPE Formalin fixed paraffin embedded FSC Forward scatter GE Gene expression GOBO Gene expression-based outcome for breast cancer online GPC Glycerophosphocholine HER2 Human epidermal growth factor receptor 2 hESC Human embryonic stem cells HR MAS MRS High resolution magic angle spinning magnetic resonance spectroscopy IDC-NOS Invasive ductal carcinoma-not otherwise specified IHC Immunohistochemistry ILC Invasive lobular carcinoma LCIS Lobular carcinoma in situ MR Magnetic resonance MRI Magnetic resonance imaging MRS Magnetic resonance spectroscopy MS Mass spectrometry NOD SCID Non-obese diabetic severe combined immunodeficiency NSG NOD SCID gamma OXPHOS Oxidative phosphorylation PAM50 Prediction analysis of microarrays 50 genes PCho Phosphocholine PDX Patient derived xenograft PET Positron emission tomography FEC 5-fluorouracil, epirubicin and cyclophosphamide PR Progesterone receptor Ptd-Cho Phosphatidylcholine qRT-PCR Quantitative real time polymerase chain reaction RF Radiofrequency RNA Ribonucleic acid ROR Risk of recurrence RP-LC Reverse phase liquid chromatography SDS-PAGE Sodium dodecyl sulfate polyacrylamide gel electrophoresis SERD Selective ER downregulator SERM Selective ER modulator SILAC Stable isotope labeling with amino acids in cell culture SNP Single nucleotide polymorphism SSC Side scatter TCA Tricarboxylic acid cycle TDLU Terminal ductal lobular unit TIC Tumor initiating cells TN Triple negative TNBC Triple negative breast cancer TNM Tumor size, nodal status, metastasis

Introduction

Anatomy and histology of the normal breast The human mammary gland is organized into a tree-like structure composed of hollow, ductal branches and lobes that are surrounded by adipose and connective tissue (Figure 1). The terminal duct lobular units (TDLU) are the functional units of the breast where milk is produced. The branching ductal network is comprised of two epithelial cell types; an inner layer of polarized luminal epithelial cells that borders the lumen and an outer layer of myoepithelial cells, separated from collagenous stroma by a laminin-rich basement membrane. The TDLU is composed of terminal ducts and clusters of smaller lobules that comprise substructures called acini or ductules. Luminal epithelial cells in the acini synthesize milk during lactation, while one of the main functions of myoepithelial cells is to the ducts and push milk out of the nipple [3]. The breast stroma comprises of a mixture of cell types, such as fibroblasts, adipocytes, immune cells and endothelial cells [4].

Figure 1. Anatomy of the breast.

A cross-section of a normal duct showing an inner layer of luminal epithelial cells, surrounded by a layer of myoepithelial cells and an outer basement membrane. The development of breast cancer involves progression through several pathological stages, including pre-malignant lesions (DCIS), invasive carcinomas and eventually metastatic carcinomas. Reprinted from Marshall with permission [1].

Breast cancer epidemiology Breast cancer is by far the most frequent cancer among women with an estimated 1.67 million new cases per year worldwide [5], and in Norway; about 3000 women develop breast cancer annually [6]. As illustrated in Figure 2, the increase in breast cancer incidence was observed from the mid-1990s to 2005, while the incidence rate has been more stable over the last two decades. Improvements in mammography screening programs and early diagnosis have been important causes of the observed increased incidence rate, especially of preinvasive tumors such as Ductal Carcinoma In Situ (DCIS). This, together with improved tumor classification and therapeutic options are likely to explain the recent decline in mortality. In Norway, the breast cancer mammographic screening program of women aged 50-69 started in 1995 and became national in 2005.



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