Wissenschaftliche Highlights der GSF 2007

H
Forschungszentrum für Umwelt
und Gesundheit GmbH
in der Helmholtzgemeinschaft
Wissenschaftliche Highlights
der GSF 2007
Wissenschaftlich-Technische Abteilung
Abfrage April 2007
Institut / Selbst. Abteilung / KKG / Nachwuchsgruppe:
Pathology
FE-Nr.: 70311
Kontaktperson für Rückfragen:
Michaela Aubele [email protected]
4132
Titel des Highlights:
PTK (protein tyrosine kinase)-6 and Her2 & 4, but not Her1 & 3 predict long term
survival in breast carcinomas
Keywords:
Her receptor family, protein tyrosine kinase 6 (PTK6), breast cancer, prognosis
Kernaussage des Highlights in einem Satz:
The cytoplasmic tyrosine kinase PTK6 is of prognostic relevance in breast cancer
and may represent a novel therapy target
Darstellung des Highlights:
The HER receptors (in particular Her2/neu) are of therapeutic and prognostic significance in
breast cancer, and their function is modulated by cytoplasmic tyrosine kinases like PTK6
(brk). It has been shown that the monoclonal antibody trastuzumab directed against Her2/neureceptor is therapeutically active in Her2/neu overexpressing breast carcinomas. However, a
consistent number of Her2/neu-positive tumors are not responsive to this antibody therapy,
indicating that simple oncogene overexpression may not account for the full malignant
phenotype.
In this study we investigated the protein expression of the HER receptor family
(HER1/EGF-R; HER2/neu; HER3; HER4) and the cytoplasmic tyrosine kinase PTK6 in
archival tissue from 193 breast carcinomas, and tested the association between markers and
patient prognosis.
In multivariate survival analysis for a metastases-free survival of patients (longer than
240 months) the stepwise selected parameters were tumor size, PTK6 protein expression, and
number of positive lymph nodes.
We demonstrated that PTK6 is a prognostic marker of metastases-free survival in
breast cancer, and is independent of the classical morphological and molecular markers of
lymph node involvement, tumor size, and HER2 status. Therefore, we hypothesise that PTK6
1
could be a cytoplasmic molecule influencing the biological response of HER receptor
signaling, and may be usefull as novel therapeutic target in breast carcinomas.
Michaela Aubele, Gert Auer, Axel K. Walch, Alison Munro, Mike J. Atkinson, Herbert
Braselmann, Tommy Fornander, John M. S. Bartlett. 2007. PTK (protein tyrosine kinase)-6
and HER2 & 4, but not HER1 & 3 predict long term survival in breast carcinomas. Br J
Cancer 96, 801-807.
Bezug zur GSF-Strategie:
Translational Research, Novel Target for Breast Cancer Therapy
GSF-interne Kooperationspartner, mit denen das Highlight ggf. erarbeitet
wurde:
H. Braselmann, GSF - IMS, FE 70431
2
PTK (protein tyrosine kinase)-6 and Her receptors
in breast cancer
z About 30 % of breast carcinomas show overexpression of the
Her2/neu cell mebran receptor
z Her2/neu antibody therapie (Trastuzumab) response:
Trastuzumab Monotherapy: 15-35%
Trastuzumab + Chemotherapy: up to 70%
searching for
novel / additional therapy targets?
Pathology
PTK (protein tyrosine kinase)-6
z cytoplasmic non-receptor tyrosine kinase (BRK);
expression = epithelial-specific
z elevated expression was found in breast cancer cell lines
and in 2/3 of primary breast tumors
z in vitro studies showed, that PTK6 overexpression:
- increases Her3 phosphorylation and Akt activation
- sensitizes cells to EGF and co-precipitates with Her3
z Function of PTK6 is unknown
z PTK6 protein possesses:
protein tyrosine kinase domain
SH2 domain
SH3 domain
regions enable it to protein-protein interactions
Pathology
Results
z we found PTK6 overrepresented on DNA, mRNA and on protein level
in breast carcinomas
AIB1.PCR1
AIB1.2
ADA
AIB1.1
BCAS1
ZNF218
ZNF217
GNAS
MMP9
TOP1
SNAI1
NCOA3
PTPN1.2
PTPN1.1
Screening of
Chrom. 20q genes
PPIAL2
PTK6
Immunhistochemie
gene copy number
Born et al. J Pathol 2006
Pathology
Results
Multivariate survival analysis
classification of patients into 3 different risk groups according to their parameters:
tumorsize / PTK6 protein expression / lymph node status
low risk
1,0
low
91% event-free
medium risk
probability
probability
0,8
medium
71% event-free
0,6
overall
high risk
0,4
high
43% event-free
p<0.0001
0,2
0
50 distant recurrence-free
100
150
200
survival
(months)
250
distant recurrence-free survival (months)
Brit J Cancer 2007
Pathology
Summary
PTK6
z expression is correlated with expression of Her receptors
z its protein expression correlates with clinical
outcome of patients
z may modify HER receptor signaling in tumor cells and,
therefore, may represent a novel therapy target in breast cancer
Pathology