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Receptor Biology Laboratory, Imperial Cancer Research Fund Oncology Unit, Imperial College School of Medicine, London W12 ONN [ R. S., W. J. G.], and Hedley Atkins/Imperial Cancer Research Fund Breast Pathology Laboratory, Guy’s Hospital, London SE1 9RT [ C.E.G., D.M.B.], United Kingdom
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ABSTRACT |
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overexpression. |
Introduction |
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60% of
breast cancers, correlates inversely with the presence of ERs, and is
an indicator of poor prognosis in most studies. Overexpression of
c-erbB-2 in breast and in other cancers is well documented. In breast
cancer, the gene is amplified in 20% of cases leading to receptor
overexpression, which correlates with a hormone-independent, more
aggressive phenotype and is an overall indicator of poor prognosis. We
know less about c-erbB-3, however, which has also been shown to be
overexpressed in a proportion of several types of malignancies
(4)
. The c-erbB-3 receptor is overexpressed in 20% of
infiltrating breast cancer cases and in about one-third of ductal
carcinoma in situ of the breast, presumably as a result of
an increase in gene transcription as gene amplification has not been
observed. Thus far, in the studies reported to date, c-erbB-3 status is
not associated with survival and so has not been demonstrated to be
useful as a prognostic indicator. Research into the role of c-erbB-4 in
breast cancer is still in its early stages. The c-erbB-4 protein is
expressed in normal breast epithelial cells in humans (5
, 6)
and in mice (7)
. The c-erbB-4 protein was shown
to be expressed in breast cancers by immunocytochemical staining
(5)
and at the mRNA level by in situ
hybridization analysis (4)
. mRNA expression has also been
reported to be present at relatively high levels in the T47D,
MDA-MB-453, BT-474, and H3396 breast cancer-derived cell lines
(8)
. In human primary breast cancers, c-erbB-4 mRNA
expression was found to be positively associated with expression of ERs
and the Ki67 antigen and negatively associated with epidermal growth
factor receptor protein expression (9)
. The present pilot
study was, therefore, undertaken to determine the prevalence and
pattern of c-erbB-4 protein expression in a series of breast cancer
cases. These had been analyzed previously for the expression of the
other type I growth factor receptors and for some of the ligands of the
EGFR, including TGF- (10)
and amphiregulin and the
orphan ligand cripto. The lymph node status, histological type and
grade of tumor, and ER status had also been documented. Our aim was
then to ascertain whether any correlations were found between c-erbB-4
expression and these variables and to determine whether c-erbB-4 was
implicated in breast cancer development or could act as a useful
molecular marker in breast cancer prognosis. |
Materials and Methods |
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, and amphiregulin
expressions were determined as described previously (12)
.
c-erbB-4 protein was detected using the mouse monoclonal HFR-1
antibody, which was raised against the intracytoplasmic domain of
c-erbB-4 protein or in some cases with the C18 rabbit polyclonal
antibody (Santa Cruz Biotechnology). HFR-1 was used at a concentration
of 1 µg/ml (5)
. Both a negative control, in which the
primary antibody was replaced with TBS, and a positive control were
included with each batch of staining. Immunohistochemistry using the
streptavidin-biotin immunoperoxidase technique was carried out on
sections pretreated with Protease XXIV (Biogenex) for 5 min. Peroxidase
activity was demonstrated using diaminobenzidine, giving a red/brown
end product.
Evaluation of Immunoreactivity for c-erbB-4 Expression Using the
HFR-1 Antibody.
Normal and malignant breast epithelial cells were examined for
the presence of positive membrane, cytoplasmic, and nuclear staining.
The scoring system for cytoplasmic expression takes into account both
the percentage of positive cells and the intensity of staining and has
been used previously (11)
. The percentage of positive
cells was scored as: 0, no positivity; 1, up to 25% positive; 2,
26–50% positive; 3, 51–75% positive; and 4, >75% positive. The
intensity of immunoreactivity was scored as: 1, weak positivity; 2,
moderate positivity; and 3, strong positivity. The two scores were
added to obtain a total score. Nuclear immunoreactivity, when present,
was evaluated as the proportion of positive nuclei only and, therefore,
was given a score of between 1 and 4. For the purposes of statistical
analysis, the cases given a score of 1 were combined with those cases
that had no nuclear expression. Expression of c-erbB4 at the membrane
was recorded as being present or absent.
Statistical Analysis.
The 
2 test were used to assess the association
between the level of c-erbB-4 expression and the other parameters
studied. The clinical and molecular characteristics of the 178 breast
cancers and the categories used for the statistical analysis are
described in Table 1
. The curves for relapse-free and overall survival were produced using
the method of Kaplan-Meier, and the ability of c-erbB-4 expression to
predict prognosis was evaluated using log-rank analysis.
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Results |
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of variable intensity as compared with
normal breast tissue (Fig. 1A)
. Membrane accentuation of
cytoplasmic reactivity was noted in some cases, as was nuclear
reactivity (Fig. 1D)
. There were significant associations
between the level of expression of c-erbB4 in the membrane, cytoplasm,
and nucleus (Table 2)
.
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when present
in the same section. Using the scoring system detailed in "Materials
and Methods," the tumors were divided into three main groups based on
their cytoplasmic reactivity score. Scores of 7 were considered to
represent overexpression of c-erbB-4, cases with scores ranging from 4
to 6 displayed levels equal to that of the adjacent normal tissue, and
scores of less than or equal to 3 were considered as having lower
c-erbB-4 expression than normal. By these criteria, 13 cases (7%)
showed overexpression, 134 cases (75%) were equal to normal levels,
and 32 cases (18%) had levels of expression less than normal.
Nuclear immunoreactivity for c-erbB-4 was analyzed independently of the
cytoplasmic reactivity. A total of 87 cases (49%) showed some nuclear
immunoreactivity, which had a diffuse pattern in most cases. Nuclear
membrane reactivity was also observed in some cases. Occasionally, the
morphologically normal breast epithelial cells adjacent to the tumor
also displayed positively stained nuclei, but this was seen in fewer
than 5% of cases. To ensure that detection of c-erbB-4 in the nucleus
was not a result of cross-reactivity with some other protein antigen, a
few sections that were positive with the HFR-1 antibody were
immunostained with C18 antibody (Santa Cruz Biotechnology). This
antibody has been raised against a different epitope (reported to be
the COOH terminus) of c-erbB-4. Similar nuclear reactivity to that seen
with HFR-1 was observed in all cases (Fig. 1, E and F)
. Nuclear staining was further evaluated by estimating the
percentage of positively stained malignant cells in the section.
Although nuclear reactivity was recorded as four groups based on the
percentage of cells positive, for the purposes of statistical analysis
the cases were divided into two groups: those with no nuclear
expression or <25% of nuclei positive (91 of 178, 51%); and a second
group of cases with >25% of nuclei positive (87 of 178, 49%). Cell
membrane immunoreactivity, which was documented as present or absent,
was seen in 52 of 178 cases (29%) and was analyzed independently of
the cytoplasmic score.
The degree of cytoplasmic, nuclear, and membrane immunoreactivity was
compared with the clinicopathological and biological parameters to
determine possible associations. These included: histological type and
grade of tumor; ER status and positivity for the type 1 growth factor
receptors EGFR, c-erbB-2, and c-erbB-3; and the ligands TGF-,
amphiregulin, and cripto. For the statistical analysis examining the
relationship between c-erbB-4 cytoplasmic expression and these factors,
the tumors were placed into two groups, rather than three: those
showing less than normal levels of expression (scores of 0–3); or
those showing similar to or greater than normal levels of expression
(scores of 4–7). The reason for this was that the number of cases
showing overexpression (a score of 7) was too small for meaningful
analysis.
This analysis revealed no significant associations between c-erbB4 cytoplasmic expression and any of the other variables. Similarly, there were no significant associations between membrane immunoreactivity for the c-erbB-4 protein and the markers.
Nuclear immunoreactivity was also compared with the clinicopathological
and biological markers (Table 3)
. There was a statistically significant inverse association between
nuclear c-erbB-4 expression and histological grade of the infiltrating
ductal carcinomas (2 = 13.45;
P = 0.0012) and a positive association with
c-erbB-3 (2 = 3.85;
P = 0.05) and EGFR expression
(2 = 4.57; P = 0.033). There is also a significant positive association between
cripto (2 = 8.48;
P = 0.004), amphiregulin
(2 = 8.48; P = 0.0036), and TGF- (2 1.67;
P = 0.02) overexpression. Nuclear expression
of the c-erbB-4 protein was not significantly related to histological
type, node status, ER, or c-erbB-2 overexpression.
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The log-rank test of the survival data derived for the cases showing underexpression of cytoplasmic c-erbB-4 compared with the rest of the group did not reveal any significant differences. Similarly, neither nuclear or membrane reactivity seemed to influence relapse-free or overall survival in this series of patients (data not shown).
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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The function of c-erbB-4 in these settings is still unclear. In normal breast, neuregulin-1 (heregulin) implants induced proliferation and differentiation of mammary epithelium (18) . In models of breast cancer, activation of c-erbB-4 appears to be associated with signals inducing differentiation (such as lipid droplet formation and casein production) and apoptosis. Interpretation of these results is complicated, however, by the multiple interactions of the ligands and receptors and their differing relative abundance in each model system. In addition, even when the content of c-erbB-4 was known, these studies were performed before it was apparent that at least four splice variants of the gene could be expressed. These variants confer on the protein sensitivity to proteolytic cleavage or the ability to selectively activate the phosphatidylinositol 3-kinase signaling pathway. Recently, these issues have begun to be explored by analysis of mRNA expression in breast cancer by PCR (19) and by isotype-specific antisera.3
The finding here of a common nuclear localization for the c-erbB-4 protein in the cancer cells was unexpected. The fact that two antibodies raised against different epitopes on c-erbB-4 showed similar immunoreactivity indicates that this is probably a true localization rather than attributable to nonspecific binding. In a small proportion of cases (<5%), nuclear reactivity was seen in the morphologically normal breast epithelium adjacent to the tumor. Confirmation of the presence of c-erbB-4 in the nuclei of normal breast epithelial cells not potentially influenced by the tumor environment can be obtained by studying tissues derived for reduction mammoplasty. In addition to breast cancer, nuclear positivity for c-erbB-4 has been observed occasionally in the cells of the distal convoluted tubules of the kidney (5) and the nuclei of endometrial stromal cells.4 It is not currently known whether nuclear localized c-erbB-4 will be present in ductal carcinoma in situ of the breast.
In this study, nuclear immunoreactivity was significantly inversely
correlated with histological grade, implying that the presence of
c-erbB-4 in the nucleus is related to tumor differentiation. A positive
association with c-erbB-3 expression was also observed, which is
concordant with a recent report wherein a direct association between
c-erbB-4 mRNA levels and c-erbB-3 mRNA levels as detected by reverse
transcription-PCR was observed (9)
. We did not observe any
association between either cytoplasmic or nuclear c-erbB-4
immunoreactivity and ER positivity. This is in contrast to a previous
study in which a positive correlation with c-erbB-3 and c-erbB-4
positivity has been reported (9)
. There was no statistical
association between the level of c-erbB-4 expression and overall
survival. We also found a positive association between nuclear
c-erbB-4 expression and the ligands TGF-, amphiregulin, and cripto.
The former two proteins bind to the EGFR and not to c-erbB-4 (or
c-erbB-3), but interestingly, cripto has been shown recently to
stimulate the phosphorylation of c-erbB-4 indirectly through an as yet
uncharacterized mechanism (20)
.
At present, there are few hypotheses suggesting the function of nuclear growth factors or their receptors. After interaction with the ligand, internalization of the receptor has been demonstrated only in the case of EGFR and not for the other members of the family (21, 22, 23) . In the process of receptor metabolism, recycling, and degradation, the molecules are also necessarily present in the cytoplasm. Nuclear localization of growth factors and their receptors, which has now been reported for many molecules (24) , is conceptually more difficult to explain. Nuclear localized FGF-2 has been shown to induce transcription of ribosomal genes and phosphorylation of nucleolin by binding to and stimulating the activity of protein kinase CKII (25) .
Some reports have demonstrated nuclear localization of members of the type I family of receptors and their ligands. The c-erbB-2 receptor has been detected in the nuclei of DHFR/G8 cells (NIH3T3 cells transfected with normal rat neu) by Western blotting of nuclear extracts, and immunofluorescence of isolated nuclei (26) and Amphiregulin has been shown to be present in ovarian cancer cell nuclei determined by immunostaining (27) . Indeed, Modrell et al. (28) has shown that amphiregulin binds to DNA Sepharose and localizes to the nuclei of ovarian cancer cells, and Kimura (29) has reported that Schwannoma-derived growth factor (the rat equivalent of amphiregulin) must be transported to the cell nucleus to exert its mitogenic effect, where it binds DNA and stimulates immediate early gene expression. At least one of the ligands of c-erbB-4, neuregulin-1-ß, has been shown to rapidly internalize and translocate to the nucleus in the SK-BR-3 breast cancer cell line (30) . The exact mechanism of this phenomenon has not been demonstrated, but theoretically this could occur in a receptor-dependent or independent way. In the latter case, the ligand could act as a "transporter" of the receptor to the nucleus, or the receptor in some way could help ligand to translocate to the nucleus. It is also possible that the cytoplasmic domain of the receptor moves into the nucleus once the ectodomain has undergone proteolytic cleavage at the cell surface. Both antibodies used in this work are directed to the cytoplasmic domain; therefore, we cannot answer this point at present. Additional studies using more sensitive and dynamic approaches, such as light-based detection and tracking systems in live cells using fluorescence-tagged ligands and/or receptors, are required to clarify this issue.
Nuclear localization signals are short peptide stretches with clusters of arginines and lysines that target proteins to the nucleus. An analysis of the c-erbB-4 protein sequence using the PSORT II software5 showed the presence of three putative nuclear localization signals in its cytoplasmic domain: KKKR (amino acids 681–684), PFVSRRK (amino acids 1170–1176), and PEKAKKA (amino acids 1230–1236). We are currently mutating these sites in a green fluorescent protein-tagged c-erbB-4 to address the relevance of these sites to the subcellular distribution of the receptors.
In summary, in breast cancer, c-erbB-4 nuclear immunoreactivity is frequent and seems to be associated with a better differentiated phenotype. Larger studies on the expression of the c-erbB-4 protein in breast cancer are necessary to confirm our initial observations and also elucidate more subtle associations.
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Cancer Biology Laboratory, Department of Biosciences,
University of Kent at Canterbury, Canterbury, Kent CT2 7NJ, United
Kingdom. E-mail: W.J.Gullick{at}ukc.ac.uk 
2 The abbreviations used are: EGFR, epidermal
growth factor receptor; TGF, transforming growth factor; ER, estrogen
receptor.
3 W. J. Gullick and N. R. Levinson,
unpublished observations.
4 R. Srinivasan and W. J. Gullick, unpublished
results.
5 Internet address: http://www.expasy.ch/tools/.
Received 8/19/99. Accepted 2/ 2/00.
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REFERENCES |
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and TGF ß expression in mammary carcinoma. J. Pathol., 170: 15-22, 1993.[Medline]
, amphiregulin and CRIPTO in human normal and malignant breast tissues. Int. J. Cancer, 65: 51-56, 1996.[Medline]
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C. I. Sartor, H. Zhou, E. Kozlowska, K. Guttridge, E. Kawata, L. Caskey, J. Harrelson, N. Hynes, S. Ethier, B. Calvo, et al. HER4 Mediates Ligand-Dependent Antiproliferative and Differentiation Responses in Human Breast Cancer Cells Mol. Cell. Biol., July 1, 2001; 21(13): 4265 - 4275. [Abstract] [Full Text] [PDF]
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L. M. R. Gilmour, K. G. Macleod, A. McCaig, W. J. Gullick, J. F. Smyth, and S. P. Langdon Expression of erbB-4/HER-4 Growth Factor Receptor Isoforms in Ovarian Cancer Cancer Res., March 1, 2001; 61(5): 2169 - 2176. [Abstract] [Full Text]
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V. Pawlowski, F. Revillion, M. Hebbar, L. Hornez, and J.-P. Peyrat Prognostic Value of the Type I Growth Factor Receptors in a Large Series of Human Primary Breast Cancers Quantified with a Real-Time Reverse Transcription-Polymerase Chain Reaction Assay Clin. Cancer Res., November 1, 2000; 6(11): 4217 - 4225. [Abstract] [Full Text] [PDF]
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H.-J. Lee, K.-M. Jung, Y. Z. Huang, L. B. Bennett, J. S. Lee, L. Mei, and T.-W. Kim Presenilin-dependent gamma -Secretase-like Intramembrane Cleavage of ErbB4 J. Biol. Chem., February 15, 2002; 277(8): 6318 - 6323. [Abstract] [Full Text] [PDF]
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25% nuclei positive) compared with other
parameters