Cancer Research in Switzerland - Krebsliga Schweiz

130
Interpretation
ESA treatment in patients with cancer increased on-study
mortality and worsened overall survival. For patients
undergoing chemotherapy, the increase was less pronounced,
but an adverse effect could not be excluded.
Project coordinator
Dr. Julia Bohlius
Forschungsgruppe Krebs
Institut für Sozial- und Präventivmedizin (ISPM)
Universität Bern
Finkenhubelweg 11
CH-3012 Bern
Phone +41 (0)31 631 35 10
jbohlius@ispm.unibe.ch
Carbone Giuseppina | Functional and clinical implications
of deregulated expression of ETS transcription
factors in prostate cancer (OCS 01913-08-2006)
Cancer of the prostate is a leading cause of cancer death
in Western countries. There is great need to understand
the factors governing disease progression and identify
new therapeutic strategies. Transcription factors of the
ETS family have emerged as important elements in the
pathogenesis of prostate cancer. About half of prostate
cancers harbour chromosomal translocations involving
ETS genes. ETS factors act as nodal points of various signalling
pathways controlling cell proliferation, differentiation
and survival. In many tissues, ETS factors constitute
a complex network of transcriptional regulators with biological
responses depending on the balance between factors
exhibiting similar or opposite functions. Our hypothesis
is that an endogenous network of ETS factors controls
to a significant extent the differentiation status of prostate
epithelial cells. An altered balance between these ETS
factors, which may result from environmental, genetic or
epigenetic events, could promote cell transformation and
drive tumour progression.
Objectives
The overall goal of this project was to understand the
functional and clinical implication of ETS transcription
factors in prostate cancer initiation and progression.
Methods
To reach our goals we applied an integrative approach
that combines translational and bioinformatic studies in
prostate cancer tumours with experiments in vitro in
transgenic cell lines and in vivo in mouse models. We performed
gain-of-function and loss-of-function studies using
transgenic cell lines. Cell phenotypes were evaluated
with a variety of cellular assays that measure growth, cell
cycle, apoptosis, cell migration, invasion and stem cell-like
properties. Biochemical assays such as chromatin immunoprecipitation
were used to evaluate direct promoter occupancy
by ETS factors and histone modifications in cells
and also in prostate cancer specimens. To define the ETS
transcriptional network, we applied genomic tools such as
microarray data from prostate cancer patients to perform
differential gene expression and correlation analysis.
Results
The results of our studies substantially advanced our understanding
of the functional and clinical role of ETS factors
in prostate cancer. We showed that additional ETS
factors, besides the known translocated ETS genes, are
frequently deregulated in prostate tumours and may
contribute significantly to prostate tumourigenesis. We
showed for the first time that the epithelial-specific ETS
factor ESE3 is frequently underexpressed in prostate tumours
and, in experimental models, acts as tumour suppressor
gene. Further, our studies demonstrated for the
first time the activation of ESE1 in prostate tumours.
Based on the ETS alterations identified by array and qRT-
PCR data, we divided tumours in subgroups with predominant
deregulation of either ERG, ESE1 or ESE3. A fourth
group included tumours that had normal-like levels of ETS
genes (NoETS).
Additional bioinformatic analyses were done to determine
whether distinct transcriptional profiles were associated
with the prostate cancer subgroups identified on the basis
of ETS expression patterns using differential gene expression
analysis. ERG and ESE3 tumours had robust signatures
with the largest number of differentially expressed
genes.
This analysis allowed us to uncover the transcriptional
network of selected ETS factors in prostate tumours. Further,
by integrating genomic data and functional assays
in cells, we established a direct link between aberrantly
expressed ETS factors and epigenetic reprogramming of
the prostate cancer transcriptome. An important finding
of our study was the demonstration that the Polycomb
group protein EZH2 is a direct target of oncogenic and tumour
suppressor ETS factors, like ERG and ESE3. Further,
we showed that EZH2 is a key player in transcriptional silencing
of the Nkx3.1 tumour suppressor gene. This may
represent a general mechanism linking aberrantly expressed
ETS with deregulation of epigenetic pathways and
reprogramming of prostate epithelial cell transcriptome
during tumourigenesis.
Clinical relevance for patients
The presence of prostate cancer subgroups with distinct
ETS expression patterns and biological features may have
important implications and suggests that assessment of
ETS expression levels might be useful to distinguish tumours
with different clinical outcome. Further, the link
between altered ETS factors activity and EZH2 mediated
epigenetic gene silencing may suggest selective therapeutic
strategies for prostate cancer.
Project Coordinator
Dr. Giuseppina Carbone
Laboratorio di oncologia sperimentale
Istituto oncologico della Svizzera italiana (IOSI)
Via Vincenzo Vela 6
CH-6500 Bellinzona
Phone +41 (0)91 820 03 66
Fax +41 (0)91 820 03 97
pina.carbone@irb.unisi.ch