Thesis Récepteurs des androgènes constitutivement actifs dans le

Thesis
Submitted for the degree of Philosophy Doctor of the University of Strasbourg
Récepteurs des androgènes constitutivement actifs dans le
cancer de la prostate: interconnections avec les voies de
signalisation
Constitutively active androgen receptor in prostate cancer:
interconnection with kinases pathways
Gemma Marcias
Defended on 8 December 2009
Academic Referees:
Dr. Jocelyn CERALINE, MCU-PH/ HDR : thesis director
Université de Strasbourg
Pr. Zoran CULIG: thesis co-director
Innsbruck Medical University
Pr. Olivier CUSSENOT, PU-PH : external referee
Université Paris 7
Dr. Christian SLOMIANNY: external referee
INSERM U800, Villeneuve
Dr. Cécile ROCHETTE-EGLY, HDR: internal referee
INSERM U964, Strasbourg
Pr. Jean-Pierre BERGERAT, PU-PH : examiner
Université de Strasbourg

Ms Gemma Marcias was a member of the European Doctoral College of Strasbourg during
the preparation of her PhD, from 2006 to 2009, class name Virginia Wool. She has benefited
from specific financial supports offered by the College and, along with her mainstream
research, has followed a special course on topics of general European interests presented by
international experts. This PhD research project has been led with the collaboration of two
universities: the University of Strasbourg, Strasbourg, France and the Medical University of
Innsbruck, Innsbruck, Austria.

I would like to acknowledge Pr. Jean-Pierre Bergerat, Head of the Department. I would like to
thank him for offer me the opportunity to integrate his team.
I would like to express my gratitude to my supervisor Dr. Jocelyn Céraline for guidance,
support and encouragement during my Ph.D studies. I would like to thank Jocelyn who
accepted me after our first “famous” meeting on September afternoon 4 years ago when I
arrived in Strasbourg for tourism.
I also wish to thank Pr. Jean-Emmanuel Kurtz who dedicates his precious time for revising
my manuscript.
I wish to extend my warmest thanks to my colleagues who helped me with my project in the
laboratory: Eva, Christelle and Adeline. I also thank Philippe and Sabrina for their friendly
help.
During my thesis, I had the chance to work under the co-direction of Pr. Zoran Culig at the
Innsbruck Medical University. I would like to thank the Pr. Culig for the enthusiastic
welcome that I received during the months that I spent in Innsbruck and for his kindness.
Gratitude goes to Dr. Ilaria Cavarretta for her precious advises and for her solid friendship.
Appreciation also goes to Frederic and Nora, Hannes, Martin, Kamilla and all the other
members of the group.
I would like to thank Pr. Olivier Cussenot, Dr. Christian Slomianny, Dr. Cécile Rochette-Egly
members of my committee for having kindly accepted to examine this thesis.
I would like to thank my “little-Italy in Strasbourg”: Angelita, Stefano and Giovanni.
I would also like to thank Gaëlle and Monika for their lightning speed to buy chocolate to
cheer me up!
I thank my flatmate Guillaume that stood and encouraged me during these years.
I would like to thank my friends: Philip, Francesca, Davide, Simone, Roberta, Alessandro,
Fabrizio, Giuseppe, Alice and Roberto the distance never prevented you to be present for me.
I would like to thank Leszek for his support and the nice time spent together.
I would like to express my gratitude to my family for the support that they provide me. Grazie
Babbo e Giulia di essermi stati tanto vicini, di avermi incoraggiata e sostenuta ogni giorno
durante tutti questi anni.
This project would not have been possible without the financial assistance of the association
Alsace contre le Cancer. I express my gratitude to all the members of the association for their
kindness.

Index
Introduction
Prostate cancer p.1
Epidemiology p.1
Risk factors p.1
Prostate p.3
Function and architecture p.3
Prostate development p.3
Stroma/epithelium exchange in adult normal prostate toward PCa p.4
Classification of prostate cancer p.5
The TNM System p.5
The Gleason grading system p.6
Diagnosis p.8
Digital rectal examination (DRE) p.8
The serum Prostate-specific antigen evaluation p.8
Prostate cancer gene (PCA3) marker p.9
Prostate biopsies p.9
Other biomarkers for PCa p.11
Prostate specific membrane antigen (PSMA) p.11
Urokinase like plasminogen activator receptor forms (uPAR) p.11
Early prostate cancer antigen (EPCA) p.11
Prostate cancer specific autoantibodies p.11
Transforming growth factor beta1 (TGF-β1) and interleukin-6 (IL-6) p.12

Treatments p.13
Localized PCa treatment p.13
Radical prostatectomy p.13
Radiotherapy (RT) p.13
Cryotherapy and high-intensity focused ultrasound (HIFU) p.13
Advanced PCa treatment p.14
Endocrine treatment p.14
Hormonal agents p.15
Complete androgen blockade (CAB) p.16
Antiandrogens p.16
Inhibition of 5α-reductase p.17
Intermittent androgen deprivation: androgen deprivation treatment (ADT) p.17
Adjuvant ADT after local definitive therapy p.17
Androgen deprivation and association with RT p.17
Progression of prostate cancer to hormone-independence p.19
Chemotherapy p.19
Molecular and cellular basis of androgen-independent PCa
development p.20
The hypersensitive pathway p.20
Amplification of the androgen receptor (AR) p.20
Increased AR sensitivity p.20
Increased androgen levels p.20
Broadened specificity of the AR p.20
AR mutations p.21
Co-regulators alterations p.21
Outlaw pathway p.21
Parallel survival pathways p.21
Androgen-independent cancer cells p.22
Androgen receptor p.23