Targeting insulin-like growth factor-I receptor in breast cancer [Elektronische Ressource] / Beate Christiane Litzenburger

Litzenburger

Sujets

• Biologie
• Gesundheit

Informations

• Publié par: rheinisch-westfalischen_technischen_hochschule_-rwth-_aachen
• Publié le: 01 janvier 2011
• Nombre de lectures: 17
• Langue: English
• Poids de l'ouvrage: 4 Mo

Extrait

Targeting Insulin-like Growth Factor - I Receptor in
Breast Cancer
















Beate Christiane Litzenburger





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Targeting Insulin-like Growth Factor - I Receptor in
Breast Cancer



Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der
RWTH Aachen University zur Erlangung des akademischen Grades einer Doktorin der
Naturwissenschaften genehmigte Dissertation
vorgelegt von

Diplom-Biologin

Beate Christiane Litzenburger

aus Hattingen




Berichter:
Universitätsprofessor Dr. Bernhard Lüscher essor Dr. Lothar Elling

Tag der mündlichen Prüfung: 28.06.2010

Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar.
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Acknowledgments

Acknowledgments
I would like to take this opportunity to acknowledge and thank a number of people for
their support throughout the process of my dissertation.
First and foremost, I would like to acknowledge my mentor and advisor Professor Dr.
Adrian V. Lee at Baylor College of Medicine for making this study possible. His steadfast
support and encouragement over the years, trust and dedication has been truly a source of
learning and inspiration throughout my training. He was always willing to devote his time and
energy to encourage and mentor me. He has shown me to work on challenging problems and
not to give up. I will be forever indebted to him for his graciousness and excellence as a
mentor, for his guidance, help, encouragement and his commitment to my thesis.
In addition, I would also like to express my gratitude to my advisor and mentor
Professor Dr. Bernhard Lüscher at the Technical University of Aachen for giving me the
opportunity to carry out this thesis in Dr. Adrian Lee‘s laboratory. His encouragement, advice,
suggestions, and support have truly been helpful during my work on this project.
I would have not been able to complete this thesis without the support of all the
members of Dr. Lee‘s lab. I would especially like to thank Dr. Hyun-Jung Kim, Dr. Xiaojiang
Cui, and Dr. Robert Dearth for coming up with ideas which always seemed to solve my
experimental problems. Their patience in teaching me was invaluable when I had just started
working in the lab. Dr. Hyun-Jung Kim was my first post-doctoral mentor with whom I
worked on the first paper I ever published. I have been fortunate to have had wonderful lab
members. Dr. Petra den Hollander helped me a lot with great humor and great suggestions and
a broad knowledge in breast cancer research. Many thanks to other members and past-
members of the Lee lab Dr. Isere Kuiatse, Angelo Casa, Adam Potter, Yu-Fen Wang, Bonita
Chang, Ilias Patanam, Caroline Schönherr, Ora Britton, David Delgado and for their
assistance, help, expertise, advice and support. They all made the work that much more
enjoyable. They cheered me up many times when the experiments did not go the way they
were supposed to and they have shown me many tricks that helped improve my work.
Joan Carboni, Bristol Myers Squibb, is greatly acknowledged for providing us with
BMS-754807. Further thanks to Professor Dr. Steffi Oesterreich and her lab for their help and
support. Dr. Österreich graciously extended her mentorship and scientific expertise to me. I
would specifically like to thank Mike Toeneff, graduate student in Professor Dr. Yi Li‘s lab.
Without him I would have not be able to learn and perform TVA technology experiments. In
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Acknowledgments

addition, I would not be able to finish this thesis without the great help and support of Dr.
Anna Zsimelson, biostatistician, and Dr. Chad Creighton, bioinformatician in the Sue and
Lester Smith Breast Center. Special thanks to Professor Dr. Jenny Chang and Professor Dr.
Mike Lewis for providing the human tumorgrafts. Dr. Chang‘s and Dr. Lewis‘ lab patiently
assisted me in mouse transplantations and taught me new techniques. Finally, I would like to
thank all the graduate students and members of the Sue and Lester Smith Breast Center and
the Dan L. Duncan Cancer Center for providing a unique training environment. It really was a
pleasure to train at such an exclusive institution.
On a more personal note, I would like to thank my wonderful family, especially my
parents Karin and Lothar Litzenburger for their continual support and encouragement during
the making of this thesis. They made many personal sacrifices to afford me the opportunity to
study and train at Baylor College of Medicine. Though not physically present their belief in
me made this entire work accomplishable. I especially have to thank my sister, Ulrike
Litzenburger who has been very supportive and encouraging since she is also pursuing her
PhD in Germany. My family has encouraged me at times when I needed it most. I owe special
gratitude to Antonio Mendoza for all his unwavering support, encouragement, and his
motivation to strive for excellence. The incredible amount of patience he had with me made
my life easier and more enjoyable during this time. Last but not least, thanks to all my friends
who made my life as a PhD student an incredible time.
This work was generously supported in part by a fellowship of the German Academic
Exchange Program (DAAD) and a Pre-Doctoral Fellowship from the Department of Defense
Breast Cancer Research Program; DAMD-W81XWH-08-1-0220.










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Abstract

Abstract
Insulin-like growth factor-I receptor (IGF-IR) is integral to cancer cell proliferation, survival,
migration, and invasion, and resistance to anti-cancer therapies in many human malignancies
including breast cancer. Within the last few years several drugs targeting IGF-IR have entered
clinical trials and are showing promising early results. One of the integral goals of my thesis
is to identify patients who are most likely to benefit from therapy. The Lee Laboratory
previously reported an IGF gene expression signature, based upon genes induced or repressed
by IGF-I, which correlated with poor prognosis in breast cancer. Confirming that this
signature can measure IGF activity, I report here that the signature is reversed in three
different cancer models (cell lines or xenografts) treated with three different anti-IGF-IR
therapies. The Lee laboratory originally reported that the IGF signature was present in triple-
negative human breast cancers (TNBC), and I found here that the signature is similarly
present in TNBC cell lines. Supporting a role for IGF-IR signaling in this subtype of breast
cancer, I found that TNBC cell lines were especially sensitive to an IGF-IR tyrosine kinase
inhibitor (BMS-754807), and that sensitivity was significantly correlated to expression of the
IGF gene signature. Consistent with this, comparative gene expression analysis among the
most resistant and sensitive cell lines identified 114 differentially expressed genes which
identified TNBC as being sensitive. To examine this association further we determined levels
and activity of the IGF-IR in several recently developed primary human TNBC tumorgraft
models. I found high activity in many models, and chose the TNBC model MC1, which had
the highest levels of both IGF signature score and IGF-IR expression and activity, for testing
an anti-IGF-IR tyrosine kinase inhibitor (BMS-754807) in vivo. MC1 tumorgrafts treated with
BMS-754807 as a single agent showed growth inhibition, and in combination with
chemotherapy tumor regression occurred until no tumor was palpable. This regression was
associated with reduced proliferation, increased apoptosis, and mitotic catastrophe. These data
provide a clear biological rationale to test anti-IGF-IR therapy in combination with
chemotherapy in patients with TNBC.
While IGF-IR activity is elevated in TNBC, in vitro cell culture evidence suggests an
interaction between IGF-IR and ErbB2 (otherwise known as HER2). To examine crosstalk
between IGF-IR and ErbB2 in mammary tumorigenesis in vivo, I used two models of mouse
mammary tumorigenesis, MMTV-CD8-IGF-IR (a constitutively active IGF-IR) and MMTV-
ErbB2. Bi-transgenic (bigenic) mice expressing both CD8-IGF-IR and ErbB2 developed
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Abstract

mammary tumors significantly faster than mice expressing either transgene alone.
Histological analysis showed that ErbB2 tumors were predominantly adenocarcinomas, CD8-
IGF-IR tumors were mixed adenosquamous carcinomas, and interestingly, bigenic tumors
showed a phenotype resembling both oncogenes. All tumor types contained CK8-positive
luminal epithelial cells. Interestingly, markers of myoepithelial (CK14) and progenitor (CK6)
cells were only detected in mammary tumors arising from MMTV-CD8-IGF-IR mice and
bigenic mice. This data is consistent with the notion that expression of IGF-IR in the
mammary gland of transgenic mice may results in expansion myoepithelial cells expressing
CK14 and progenitor cells expressing CK6 thus resulting in a mixe