Cancer Research in Switzerland - Krebsliga Schweiz

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Beermann Friedrich | In vivo screening of candidate
genes in melanoma (OCS 01500­02­2004)
Melanoma is a malignant tumour arising from melanocytes,
which are pigment cells derived from the neural
crest. In the mouse, melanoma does not occur spontaneously,
and, thus transgenic mouse models are used to address
genetic changes leading to melanomagenesis or to
study melanocyte development. In this project we wanted
to address the role of candidate genes, first in melanocyte
biology and homeostasis and later in melanoma development.
We used transgenic mouse models to analyze the
Notch signalling pathway in normal melanocyte biology,
and to address the lack of the oncogene c­Myc during
melanocyte development. Moreover, we addressed the
relevance of b­catenin directly in a mouse model of melanoma.
Notch signalling: Notch has been shown to be expressed
in mouse melanocytes and human melanoma. Using
transgenic mouse models, we showed that deletion of
Notch signalling in the melanocyte lineage induces precocious
hair greying, the intensity of which depends on the
number of deleted alleles of Notch1 and Notch2. Further
histological analysis showed that this is due to a loss of
melanocyte precursors as well as melanocyte stem cells
after birth. This confirms that Notch signalling affects hair
pigmentation and melanoblast population in a gene dosage­dependent
manner. When we overexpressed Notch
in melanocytes, we could not prevent normal hair greying
or induce melanoma tumours, indicating that Notch signalling
by itself is not sufficient for melanoma formation.
The c-Myc oncogene: c­Myc is expressed in many tumours,
including melanoma. To understand its role in melanocytes,
we removed it specifically in a transgenic mouse
model. Removal of c­Myc leads to a hair greying phenotype
that is not due to an effect in stem cells. In contrast
to Notch, the phenotype is caused by a problem in proliferation
during midgestation. These results indicated that
c­Myc is an important player in melanocyte biology, and
we plan to address its role in a mouse model of melanoma.
b-catenin: This protein is part of the Wnt signalling pathway
and has been reported to be mislocalized in human
melanoma. In collaboration with Lionel Larue’s group
(Orsay, France), we used mice that express a stable form
of b­catenin that leads to repression of the tumour suppressor
p16 by binding to its promoter. Double transgenic
animals expressing both an activated N­Ras oncogene
and an activated b­catenin had a high incidence of melanoma
with a short latency period. Histopathological analysis
suggested that most melanomas arose from melanocytes
located in the hair follicles. The results thus reveal
that synergy between the Wnt and mitogen­activated
protein (MAP) kinase pathways (due to activated N­Ras)
may represent an important mechanism underpinning the
genesis of melanoma.
Project coordinator
Dr Friedrich Beermann
Institut suisse de recherche expérimentale
sur le cancer (ISREC)
Faculté Sciences de la vie
EPF de Lausanne (EPFL)
Station 19, Bâtiment SV
CH­1015 Lausanne
Phone +41 (0)21 693 07 27
friedrich.beermann@epfl.ch
Bentires­Alj Mohamed | Role of GAB2/SHP2
and 11q13 amplification in breast cancer
(OCS 01922­08­2006)
Each year 1.1 million new cases of breast cancer will occur
among women worldwide, and 400,000 women will die
of this disease. Although progress has been made in understanding
breast tumour biology, most of the relevant
molecules and pathways remain undefined. Their delineation
is critical to a rational approach to breast cancer therapy.
This project focuses on the roles of the signalling proteins
GAB2/SHP2 (part 1) and on amplification of the chromosomal
region 11q13 (part 2) in breast cancer. To address
these questions, we used a combination of 3D cultures
and xenograft models. In the first part, we found that inhibition
of SHP2 dramatically reduces proliferation and reverses
the invasiveness of transformed breast cells grown
in 3D cultures. Moreover, SHP2 knockdown after tumour
formation blocks tumour progression. In the second part,
we found two highly defined genomic regions of 11q13
amplification in breast tumours and identified 8 genes
that are co­amplified and co­overexpressed in these tumours.
Taken together, our studies revealed potential
therapeutic targets for the treatment of breast cancer.
Project coordinator
Dr. Mohamed Bentires­Alj
Friedrich Miescher Institut für
biomedizinische Forschung (FMI)
Maulbeerstrasse 66
CH­4058 Basel
Phone +41 (0)61 697 40 48
Fax +41 (0)61 697 39 76
bentires@fmi.ch
Brunner Thomas | Characterization and role of
extra-adrenal glucocorticoid synthesis in colorectal
cancer (OCS 02025­02­2007)
Glucocorticoids are important immunoregulatory steroids,
produced mainly in the adrenal glands. However, our
past research demonstrated that the epithelial cells of the
intestinal crypts are capable of producing glucocorticoids
in response to immune cell activation and that intestinal
glucocorticoids contribute to the control of local immune
responses. The aim of this study was to investigate
whether colon carcinoma can produce glucocorticoids,
how tumour glucocorticoid synthesis is regulated and
whether tumour­derived glucocorticoids actively suppress
immune cells.
The expression and induction of transcription factors and
enzymes involved in the synthesis of cortisol from cholesterol
in colon carcinoma cell lines as well as primary tumours
was investigated using quantitative PCR and luciferase
reporter assays. The role of the transcription factor
LRH­1 (liver receptor homolog­1) in the regulation of tumour
glucocorticoid synthesis was assessed using overexpression
and RNA interference. Cortisol production was
measured using radioimmunoassay, thin layer chromatog­