Download Fundamental research on breast cancer in Belgium

Fundamental research on
breast cancer in Belgium
Rosita Winkler
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Medline search for « breast cancer » and Belgium
limits: english, posted in the last 5 years.
Result: 484 papers - fundamental / clinical according to the abstracts ????
Identified the following topics
– A. The breast cancer cell :
1.
2.
3.
4.
The estrogen receptor (ER)
ERBB2 gene
Expression of other breast cancer associated genes
Breast cancer genomics
B. Invasion, metastasis
1. Epithelial to mesenchymal transition (EMT)
2. Proteases
3. Metastasis
1. Estrogen Receptor 
(G. Leclercq, Bordet Inst.)
P295
ER17p
T311
The P295-T311 sequence:
involved in ER transcriptional activity and stability
Calmodulin (CaM) binding site ->
transcriptional activity, stability
ER17p
ER17p: estrogenic response in ERexpressing breast cancer cells
proliferation, transcription
ER expression
CaM binding
Binds ER
Dissociates the ER /HSP70 complex-> activation of ER
hypothesis: P295-T311 sequence in the full length ER has a repressive
function
Hypothesis: ER17p could be produced endogenously by ER
degradation by the proteasome and exert estrogenic effects in breast
cancer cells
; production could be enhanced by treatment with hormone and
hormone agonist -> sustained estrogenic effect.
2. Mechanisms of ERBB2/HER2
overexpression in breast cancers
In ± 20% breast
cancers erbB2/HER2
protein level is very
high.
Main mechanisms:
-gene amplification
-Increased
transcription rates
HER2/ERBB2 gene amplification
(Vanden Bempt I., De Wolf-Peeters C, KUL)
Characterization of the ERBB2 amplicon Identification of 4 chromosomal regions (≠ ERBB2 gene) overexpressed in ERBB2 gene amplified breast cancers; ex : MMP9
Other co-amplified chromosomal regions but no pattern common to all
breast cancers with ERBB2 gene amplification.
High level over-expression associated with gene amplification not with
chromosome 17 polyploidy
ERBB2/HER2 gene expression
regulation (ULg)
ERBB2
Identification of :
•Several enhancer regions, bound by
•Activator proteins - AP-2 family transcription factors overexpressed in ERBB2 positive breast cancer cells and in
subpopulation of ERBB2 positive primary breast cancers
3. pRB/E2F: regulate the expression of Brip1,
CHK1 genes in breast cancers: (Verstuyf A., KUL)
S-phase - proliferation
Brip1/BRCA1
Brip1 - (BRCA1 interacting protein) / CHK1
mutations -> increased breast cancer risk.
Brip1 and CHK1 expression:
•associated with cell proliferation
•controlled by E2F transcription factor
•Brip1 Increased in grade 3 ER-/PR-/HER2+ cancers
•CHK1 increased in grade 3 ER-/PR-/HER2- cancers
A.4 Identification of new breast cancer susceptibility
genes: rat model (Szpirer, ULB)
10-15% of human breast cancers are associated with susceptibility
genes - only 30% of these have been identified. How identify low
penetrance genes?
Rat mammary tumours interesting model :
•similar developments and histological features as human breast cancers
•strongly hormone dependent
•no virus involvement
•susceptible and resistant strains
Comparison of the genome of resistant / susceptible strains:
•Different genes involved in chemically/hormone induced cancers
•Different loci control tumour multiplicity, latency, and
aggressiveness.
B. Breast cancer cells invade
and metastasize
1. They acquire the capacity to move (EMT)
2. They produce or stimulate the stromal cells to produce
proteases necessary for invasion, angiogenesis,
metastasis
3. They form distant metastasis
Epithelial to Mesenchymal
Transition - EMT
(G. Berx Ghent, C. Gilles, Liège)
Epithelial cells are tightly bound by
“adherens junction” and their
basal surface lies on a basal
membrane.
EMT: epithelial to mesenchymal transition: transient process during
which epithelial cells loose their epithelial characteristics and acquire
mesenchymal properties: loss of adherens junctions, increased
motility; described during embryogenesis - gastrulation. Involved in
the metastatic process. Probably followed by mesenchymal to
epithelial transition (MET).
For EMT cells are
reprogrammed by reexpressing “Master
regulators”: Twist, Snail , Slug
transcription factors.
Twist, Snail , Slug:
•control embryonic EMT
•upregulated in metastatic
cancers.
• induce the replacement of
the epithelial specific proteins
by mesenchymal proteins.
Sip1 inhibits E-cadherin expression and stimulates
vimentin expression in breast cancer cells
(Berx G. RUG, Gilles C. Ulg)
Nanos
(Van Roy, Ghent)
Sip1
E-cadherin
(Berx G., Ghent)
MCP-1
(Gilles C, Lg)
Sip1
Vimentin
(Gilles C., Liège)
MMP produced by tumoral and
stromal cells during tumour
progression
Proteases and breast cancer
progression
uPAR/ uPA/PAI/plasmin system controls angiogenesis
MT1-MMP expressed by myofibroblasts in contact with the cancerous
cells
MMP2 (activated by MT1-MMP) expressed by several cell types
MT4-MMP protein is over-expressed in primary breast cancers and
node metastasis but mRNA levels are not increased
MT4-MMP over-expression accelerates the growth of mammary
cancer cells in immunodeficient mice. (Noel A., Foidart JM, Liege)
SNP in MMP8 gene promoter associated with the expression level of
the gene (Paridaens and Ye, KUL).
Bone metastasis (Castronovo, Lg)
Osteotropic breast cancer cells express bone extracellular matrix
proteins
Regulatory factors and promoter regions are being identified