2004 Summer Meeting - Amsterdam - The Pathological Society of ...

61
Expression Of The Transcription Factor CTCF In Invasive
Breast Cancer: A Candidate Gene Located At 16q22.1
E.A Rakha , C.E Paish , S.E Pinder , I.O Ellis
Nottingham, City Hospital, Nottingham University, Nottingham, United
Kingdom
CTCF is a ubiquitous 11-zinc finger protein that plays a role in gene silencing
or activation, chromatin insulation and genomic imprinting. The CTCF gene
has been mapped to chromosome band 16q22.1 that shows frequent loss of
heterozygosity in breast cancer. Because CTCF targets include TSGs and
oncogenes and it has the ability to inhibit cell growth and proliferation, it has
been suggested that it may be the target gene at the 16q22.1 especially in ductal
tumours. In the present study, tissue microarray technology was used to study
the expression pattern of CTCF immunohistochemically in 344 cases of
invasive breast carcinoma and its expression was correlated with
clinicopathological variables and patient outcome. Expression of CTCF was
detected in the cytoplasm and nuclei of the normal parenchymal as well as
malignant cells of the breast. In the malignant tissues, no significant loss or
decrease of expression was noticed in association with any specific tumour
type. There was a significant correlation between nuclear and cytoplasmic
expression of CTCF and histological grades; lower expression was associated
with grade 3 tumours. Cytoplasmic expression was associated with increased
tumour size and with the presence of vascular invasion. However, no
association was found between CTCF expression and tumour type, lymph node
stage, oestrogen receptor expression or patient outcome. Conclusion: The
current results show that CTCF, although it may play a role in breast
carcinogenesis, is unlikely to be the TSG targeted by the 16q22.1 loss in breast
cancer and thus another gene or genes at this region remain to be identified.
62
Expression and co-expression of the Epidermal Growth Factor
Receptor [EGFR] family members in invasive breast cancer
DM Abd El-Rehim , S Pinder , IO Ellis
Department of Histopathology, University of Nottingham, Nottingham,
United Kingdom
We have evaluated more than 1500 cases of invasive breast carcinoma
immunohistochemically using tissue microarray technology to examine the
expression of EGFR family receptor proteins. Overall, 20.1% and 31.8% of
cases were positive for EGFR and c-erbB-2 respectively and 45% and 45.1% of
tumors over-expressed for c-erbB-3 and c-erbB-4 respectively. The expression
of either EGFR or c-erbB-2 was associated with bad prognostic features and
with poor outcome.
c-erbB-2 had an independent prognostic effect on overall and disease free
survival in all cases as well as in the sub-set of breast carcinoma patients with
nodal metastases.
Cases were stratified according to receptors co-expression into distinct groups
with different receptor positive combinations. Patients whose tumors coexpressed
c-erbB-2 and c-erbB-3, as well as those whose tumors co-expressed
EGFR, c-erbB-2 and c-erbB-4 showed an unfavorable outcome compared with
other groups, whilst combined c-erbB-3 and c-erbB-4 expression was
associated with a better outcome. Additionally, we found a significant
association between c-erbB-4 homodimer expressing tumors and better disease
free survival. In contrast, patients with c-erbB-2 homodimer expressing tumors
had a significant poorer disease free survival compared with other cases.
These data imply that the combined profile expression patterns of the four
receptor family members together provides more accurate information on the
tumour behaviour than studying the expression of each receptor in isolation.
63
Expression of luminal and basal cytokeratins in human breast
cancer
DM Abd El-Rehim , S Pinder , IO Ellis
Department of Histopathology, University of Nottingham, Nottingham,
United Kingdom
We have examined basal and luminal cell cytokeratin expression in 1944
cases of invasive breast carcinoma, using tissue microarray technology, to
determine the frequency of expression of each cytokeratin subtype, their
relationships and prognostic relevance, if any. Expression was determined by
immunocytochemistry staining using antibodies to the luminal cytokeratins 7/8,
18 and 19 and the basal cytokeratins 5/6 and 14. Additionally, assessment of
alpha smooth muscle actin and estrogen receptor status was performed.
The vast majority of the cases showed positivity for ck 7/8, 18 and 19
indicating a differentiated glandular phenotype, a finding associated with good
prognosis, ER positivity and older patient age. In contrast, basal marker
expression was significantly related to poor prognosis, ER negativity and
younger patient age. Multivariate analysis showed that ck 5/6 was an
independent indicator for relapse free interval.
We were able to subgroup the cases into four distinct phenotype categories
[luminal, mixed luminal/basal, basal and null], which had significant
differences in relation to the biological features and the clinical course of the
disease. Tumors classified as expressing a basal phenotype [the combined
luminal plus basal and the pure basal] were in a poor prognostic subgroup,
typically ER negative in most cases.
These findings provide further evidence that breast cancer has distinct cellular
differentiation subclasses that have both biological and clinical relevance.
64
Effect of Assay Sensitivity on ER Negativity Rate
AG Douglas-Jones , JM Morgan , S Wozniac , S Hughes , S
Thomas , S Rivett , M McKenny , B Jasani
Department of Pathology, University of Wales College of Medicine,
Cardiff, United Kingdom
An audit of 2,595 consecutive routine ER results determined ER negative
rates at 3-month intervals. Sensitivity of the assay was monitored by
semiquantitative assessment (H score) of control sections. The H scores of
selected sub-groups allowed modeling of the whole set of results to show the
relationship between assay sensitivity and ER negativity rate.
The ER negativity rate varied between 7.5 and 21% and assay sensitivity varied
by 58 H score points about a mean of 116 (16%). Modeling showed that this
range of assay sensitivity would translate into a change in ER negativity rate of
14%. The model also shows how alteration of the threshold for ER positivity
changes ER negative rates.
Changes in ER assay sensitivity can account for the differences in ER
negativity rate observed in routine clinical practice.
42