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From the Department of Thoracic Surgery and Department V of
Oncology,*
Kitano Hospital, Tazuke Kofukai Medical Research
Institute, Osaka, and the Second Department of Internal
Medicine,
Ehime University School of Medicine,
Ehime, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, three members of the transmembrane 4 superfamily MRP-1/CD9,8,9KAI1/CD82,10 and ME491/CD6311 have been reported to be associated with the biological behavior of solid tumors, especially with their metastatic potential. Initially, we found that MRP-1/CD9 was recognized by the murine MAb M31–15, which inhibited cell motility.12 After the transfection of MRP-1/CD9 into human lung cancer cell lines, we demonstrated that cell motility was suppressed in the MRP-1/CD9-expressing cells.8 In addition, we showed that reduced MRP-1/CD9 protein expression was associated with metastasis and a poor prognosis in breast cancer patients13 and that reduced MRP-1/CD9 gene expression was also correlated with a poor prognosis in non-small cell lung cancer patients.14 KAI1/CD82 gene is located on human chromosome 11p11.2–13, and encodes a protein of 267 amino acids.10 Initially, it was identified by cDNA cloning as the R2 antigen, which was strongly up-regulated in mitogen-activated human T cells.15 KAI1/CD82 gene was also found to suppress tumor metastasis in a prostate cancer cell line10 and a breast cancer cell line,16,17 and thus may function as a metastatic suppressor gene.10 A clinical analysis of patients with non-small cell lung cancers also revealed that reduced KAI1/CD82 gene expression was associated with the metastasis of these tumors.18 In addition, it has been reported that ME491/CD63 is strongly expressed on the cell surface during the early stage of malignant melanoma but becomes weaker in the advanced stages.19 These findings are similar to those observed for MRP-1/CD9 and KAI1/CD82. Thus, of the many genetic markers available for evaluating the prognosis in breast cancers, MRP-1/CD9, KAI1/CD82, and ME491/CD63 gene expression may have significant value as prognostic indicators in breast cancer patients. In the present study, we investigated whether the levels of MRP-1/CD9, KAI1/CD82, and ME491/CD63 gene expression in tumor tissues are of value as prognostic factors in predicting the clinical behavior of breast cancer. Therefore, we performed a reverse transcription-polymerase chain reaction (RT-PCR) analysis to quantify the expression of these genes in tumor tissues from 109 patients with breast cancer. Immunohistochemical assays were also performed to confirm the results of the RT-PCR.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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From February 1987 to December 1995, 109 patients who underwent surgery at the Department of Thoracic Surgery of Kitano Hospital, Medical Research Institute of Osaka in Japan, were studied. The complete clinical records of all patients were available, and their histopathological diagnoses were fully documented. The postsurgical stage of each tumor was classified according to the Union International Contre Cancer TNM system.20 In total, 109 patients with breast cancer up to stage IIIB were investigated.
Ninety-five patients had undergone a mastectomy, and 14 patients had undergone a quadrantectomy followed by immediate radiotherapy. Adjuvant systemic chemotherapy was given according to the patients' estrogen receptor (ER) status. Patients who were node positive or premenopausal (n = 73) underwent chemotherapy with oral 5-fluorouracil (200 mg/day) for 2 years, and eight patients with N2 disease were also treated with six cycles of cyclophosphamide/Adriamycin. Fifty-two ER-positive patients were treated with tamoxifen (20 mg/day) for 2 years or before recurrence. Sixteen postmenopausal patients of node-negative and receptor-negative status did not have any further adjuvant treatment. Thirty-three patients had recurrences during the observation period. After the recurrence, the locoregional tumor or lymph nodes were principally resected, followed by radiotherapy. Patients with distant metastases were treated with more effective adjuvant chemotherapies, including cisplatin and pirarubicin. This report includes follow-up data as of May 1, 1997. The median follow-up period was 48.5 months.
Tumor Specimens
To ascertain the presence of cancer cells, one-half of each fresh tumor tissue specimen was immediately embedded in optimum cutting temperature compound (Miles, Kankakee, IL), and frozen sections were then cut on the cryostat to a thickness of 6 µm and immediately stained with hematoxylin and eosin. After the connective tissues were trimmed off, the other half of the tumor specimen containing greater than 80% cancer cells of all tissue cells was selected for the RT-PCR analysis.
Quantitative RT-PCR Analysis
Total cellular RNA was extracted from the frozen tumor tissues by
the acid guanidinium thiocyanate procedure.21
First-strand
cDNA synthesis was performed with 5 µg of total RNA using a cDNA
synthesis kit (Pharmacia, Piscataway, NJ) according to the
manufacturer's protocol. All of the subsequent assays were then
carried out using the same procedures as described
previously.14,18
The generated cDNAs were amplified using
primers for MRP-1/CD9 (5'-TGCATCTGTATCCAGCGCCA-3' and
5'-CTCAGGGATGTAAGCTGACT-3'), KAI1/CD82
(5'-AGTCCTCCCTGCTGCTGTGTG-3' and 5'-TCAGTCAGGGTGGGCAAGAGG-3') and
ME491/CD63 (5'-CCCGAAAAACAACCACACTGC-3' and
5'-GATGAGGAGGCTGAGGAGACC-3'). The internal control was
ß-actin (5'-GAGAAGATGACCCAGATCATGT-3' and
5'-ACTCCATGCCCAGGAAGGAAGG-3').22
All of the subsequent
assays were then carried out under conditions that yielded
amplifications of MRP-1/CD9, KAI1/CD82,
ME491/CD63, and ß-actin within a linear range.
Twenty-six cycles of PCR amplification were performed as follows:
denaturation at 94°C for 40 seconds, annealing at 60°C for 40
seconds, and extension at 72°C for 90 seconds, followed by the final
extension at 72°C for 7 minutes. The same PCR conditions were used to
amplify the ß-actin DNA. Tubes containing all of the
ingredients except templates were included in all runs and served as
negative controls. The human endothelial cell line ECV304 was used as a
positive control, which has positive expression of
MRP-1/CD9, KAI1/CD82, and
ME491/CD63.23
The amplified PCR products were
electrophoresed on a 1% agarose gel containing ethidium bromide, and
the bands were visualized under ultraviolet light followed by
densitometric analysis (Figure 1)
.
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1.0, it was considered to
indicate conserved (positive) gene expression. If the value was <1.0,
this denoted nonconserved (reduced) gene expression. Immunohistochemical Assays
To confirm the results of MRP-1/CD9 and
KAI1/CD82 gene expression on RT-PCR, immunohistochemical
studies were performed as described previously.25
Because
MRP-1/CD9 and KAI1/CD82 are not well preserved in formalin-fixed,
paraffin-embedded tissues, frozen sections were used instead. After
quenching the endogenous peroxidase activity with 0.3%
H2O2 (in absolute methanol) for 30 minutes, the
sections were blocked for 2 hours at room temperature with 5% bovine
serum albumin. Subsequently, duplicate sections were incubated for 2
hours with the anti-MRP-1/CD9 monoclonal antibody M31-1512
and the anti-KAI1/CD82 monoclonal antibody C33,26
respectively, and were then incubated for 1 hour with biotinylated
horse anti-mouse immunoglobulin G (Vector Laboratories Inc.,
Burlingame, CA). The sections were incubated with the
avidin-biotin-peroxidase complex (Vector) for 1 hour, and the antibody
binding was visualized with 3,3'-diaminobenzidine tetrahydrochloride.
Finally, the sections were lightly counterstained with Mayer's
hematoxylin (Figure 2)
. Specimens of
fibroadenoma of the breast were used as positive controls.
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(I x
PC), where I and PC represent
intensity and percentage cells that stain at each intensity,
respectively, and corresponding HSCOREs were calculated separately.
Specimens with an HSCORE of 50 were classified as MRP-1/CD9 or
KAI1/CD82-positive (+), and when HSCORE was <50, specimens were
classified as reduced (-). Statistical Analyses
The statistical significance of differences between
MRP-1/CD9 or KAI1/CD82 gene expression and
several other clinical pathological parameters was assessed by the
2
test. The disease-free survival and the overall
survival curves were constructed according to the Kaplan-Meier
method,28
and differences in the survival of subgroups of
patients were compared using Mantel's log-rank test.29
Multivariate analyses were performed using the Cox regression model to
study the effects of different variables on survival,30
and
six factors (MRP-1/CD9 status, KAI1/CD82
status, ER status, age at surgery, T status, and N status) were
studied. Scores were assigned to each variable for the regression
analysis. All P values were based on two-tailed statistical
analyses, and a P value < 0.05 was considered to
indicate statistical significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Of all 109 breast cancers studied, ME491/CD63 gene
expression was preserved and no reduced levels of ME491/CD63
DNA were detected (Figure 1)
. All of the carcinomas were evaluated to
be ME491/CD63 positive, and no statistically significant
relationships were found between ME491/CD63 gene expression
and other known prognostic factors (Figure 1C)
. Thus,
ME491/CD63 might play a different role from the other two
transmembrane 4 superfamily members in breast cancer. On the other
hand, of the 109 breast cancer patients, 73 tumors (67.0%) were
evaluated as MRP-1/CD9 positive, and 36 tumors (33.0%) were
MRP-1/CD9 negative (Figure 1A)
. Forty-four tumors (40.4%)
were evaluated as KAI1/CD82 positive, and 65 tumors (59.6%)
were KAI1/CD82 negative (Figure 1B)
. However, no
relationship was found between MRP-1/CD9 expression and
KAI1/CD82 expression (r = 0.138,
P = 0.3526, data not shown), and the expression of
these genes were independent of each other.
MRP-1/CD9 and KAI1/CD82 Protein Expression Analyzed by Immunohistochemistry
Of the 109 breast cancers studied using the immunohistochemical
method, 72 (66.0%) were classified as MRP-1/CD9 positive. In these
cases, the MRP-1/CD9 expression resembled that of benign fibroadenomas,
and the immunostaining was intense and uniform on the cell surface
membrane (Figure 2A)
. There were 37 cases (34.0%) with reduced
MRP-1/CD9 expression (Figure 2, B and C)
, and the immunostaining
from most of these tumors was heterogeneous. The MRP-1/CD9
gene expression was readily evident in those primary tumors that were
classified as positive in the immunohistochemical assays. In contrast,
the MRP-1/CD9 gene expression was weak or entirely absent in
those breast cancers that had reduced immunohistochemically detectable
MRP-1/CD9. The MRP-1/CD9 gene expression evaluated by RT-PCR
was highly associated with MRP-1/CD9 protein expression, as determined
by immunohistochemical staining (r = 0.755,
P < 0.0001) (Figure 3A)
.
Overall, the immunohistochemical results agreed well with those from
the RT-PCR assays, and 89.9% of the samples coincided exactly.
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. The KAI1/CD82 gene expression evaluated
by RT-PCR was also associated with KAI1/CD82 protein expression, as
determined by immunohistochemical staining (r =
0.803, P < 0.0001) (Figure 3B)
. These results also
agreed well with those from the RT-PCR assays, and 90.8% of the
samples coincided exactly. In cases of discrepancy, the results
from the RT-PCR analysis were used in the specimen classification. Association of Tumor MRP-1/CD9 Status with Disease-Free and 5-Year Survival of Breast Cancer Patients
As described in our results from the Western blotting analysis,
comparing survival of 109 patients with breast cancer demonstrated that
the disease-free survival rate of patients with
MRP-1/CD9-negative tumors was significantly lower than that
of patients with MRP-1/CD9-positive tumors (37.7%
versus 65.7%, P = 0.0005) (Table 1
and Figure 4A
). In particular, MRP-1/CD9
was an effective indicator of patients with early-stage tumors such as
T1, N0, stage I, and stage II (P = 0.0005,
P = 0.0007, P = 0.0168, and
P = 0.0249, respectively). In addition, the 5-year
survival rate of patients with MRP-1/CD9-negative tumors was
significantly lower than that of patients with
MRP-1/CD9-positive tumors (80.8% versus 94.0%,
P = 0.0380) (Table 1
and Figure 4B
).
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The disease-free survival rate of patients with
KAI1/CD82-negative tumors was significantly lower than that
of patients with KAI1/CD82-positive tumors (38.2%
versus 80.2%, P = 0.0065) (Table 2
and Figure 4C
). In particular, the
disease-free survival rate of patients with
KAI1/CD82-negative, early-stage tumors (ie, T1, T2, N0,
stage I, and stage II) was significantly lower than that of patients
with KAI1/CD82-positive, early-stage tumors
(P = 0.0226, P = 0.0105,
P = 0.0243, P = 0.0429, and
P = 0.0108, respectively). However, there was no
significant difference between the 5-year survival rates of patients
with KAI1/CD82-negative tumors and patients with
KAI1/CD82-positive tumors (Table 2
and Figure 4D
).
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The Cox regression model was used to evaluate the disease-free
survival and overall survival as shown in Table 3
. The MRP-1/CD9 status
(hazard ratio, 3.332; P = 0.0016), KAI1/CD82
status (hazard ratio, 2.778; P = 0.0234), ER status
(hazard ratio, 2.242; P = 0.0336), and nodal status
(hazard ratio, 3.089; P = 0.0003) were found to be
useful indicators for the disease-free survival of breast cancer
patients. On the other hand, only two variables, ER status (hazard
ratio, 6.358; P = 0.0230) and nodal status (hazard
ratio, 3.376; P = 0.0221), were significant factors for
predicting the overall survival of breast cancer patients.
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Initially, the 109 breast cancer patients were divided into four
groups according to their MRP-1/CD9 and KAI1/CD82
gene status; 34 patients had both MRP-1/CD9- and
KAI1/CD82-positive tumors, 10 patients had
MRP-1/CD9-negative but KAI1/CD82-positive tumors,
39 patients had MRP-1/CD9-positive but
KAI1/CD82-negative tumors, and 26 patients had both
MRP-1/CD9- and KAI1/CD82-negative tumors. The
disease-free survival rates of these patients were 94.1%, 40.0%,
26.9%, and 37.6%, respectively. The disease-free survival rate of
patients with tumors positive for both genes was significantly higher
than that of patients with the other three types of tumors. On the
other hand, there were no significant differences among the latter
three groups. Therefore, the 109 breast cancer patients were
reclassified into two subgroups: one subgroup with both
MRP-1/CD9- and KAI1/CD82-positive tumors and the
other subgroup with either or both negative tumors. The disease-free
survival rate of the former double-positive subgroup was significantly
higher than the latter subgroup (94.1% versus 38.4%,
P = 0.0003) (Table 4
and
Figure 4E
). In addition, the former subgroup also had a higher 5-year
survival rate than the latter subgroup (100.0% versus
84.4%, P = 0.0292) (Table 4
and Figure 4F
). The Cox
multivariate regression analysis of disease-free survival is shown in
Table 5
. This simultaneous evaluation for
both MRP-1/CD9 and KAI1/CD82 expression was found
to be a significant indicator of a poor prognosis
(P = 0.0006), and nodal status is also a
significant indicator of a poor prognosis. The other variables (age at
surgery, ER status, and T status) did not correlate with the
MRP-1/CD9 and KAI1/CD82 gene status or its
prognostic value. However, because no patients in the double-positive
subgroup have died, it is impossible to perform a Cox multivariate
regression analysis for their 5-year survival.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Both MRP-1/CD9 and KAI1/CD82 are cell surface membrane glycoproteins that are widely expressed in various normal epithelia.25 Members of the transmembrane 4 superfamily include MRP-1/CD9,8 KAI1/CD82,10 ME491/CD63,19 TAPA-1/CD81,31 CD53,32 CD37,33 and others. The members of this family have four hydrophobic transmembrane domains divided by two extracellular loops, with cytoplasmic N and C termini.34 Their extracellular loops usually have some N-glycosylation sites. This type of structure suggests that these cell surface glycoproteins might play an important role in signal transduction and may regulate cell growth, cell differentiation, cell adhesion, and cell motility.34,35 Although the precise functions of this family still remain unclear, many studies using immunoprecipitation have demonstrated the possible existence of a "tetraspan network."36 By connecting with other molecules such as integrins35,37,38 and human lymphocyte antigens,39-41 this family may organize the positioning of cell surface proteins and thus play a role in signal transduction. In addition, MRP-1/CD9, KAI1/CD82, CD63, and CD81 are considered to form complexes with each other.36 These results suggest that MRP-1/CD9 or KAI1/CD82 gene expression might be declining as the malignant tumors advance and could disrupt the tetraspan network and enable the malignant cells to acquire their metastatic potential. In fact, MRP-1/CD9 gene has been reported to be more highly expressed in a primary colon cancer as compared with its corresponding metastatic tumor using differential display cloning.42 These studies also indicated that MRP-1/CD9 and KAI1/CD82 might function as metastatic suppressor genes and are useful indicators of a poor outcome in patients with some solid tumors.13,14,18
On the other hand, the down-regulation of KAI1/CD82 gene during the progression of human prostate cancer infrequently involves a gene mutation or allelic loss.43 We also have found no mutations of MRP-1/CD9 gene in 143 resected lung tumor specimens (data not shown). To date, we believe that the mechanism underlying the reduction in the expression of these genes in tumor tissues might be an abnormal gene promoter or an abnormal down-regulation somewhere upstream in their signal pathway. Various oncogenes and oncosuppressor genes have their actions relatively upstream of the signal pathway. During the progression of these tumors, the accumulations of abnormalities might act as triggers inducing the tumors to become more aggressive.
Another interesting aspect of the current research is that our study showed that the results of MRP-1/CD9 and KAI1/CD82 gene expression as evaluated by RT-PCR agreed well quantitatively with their protein expression as evaluated by immunohistochemistry. In addition, because the results in larger-scale studies might also depend on the quality of the mRNA, it may be relatively easy to quantitate MRP-1/CD9 and KAI1/CD82 protein expression in an actual clinical setting. Our present study demonstrated that MRP-1/CD9 and KAI1/CD82 gene expression in breast cancers are important factors for predicting recurrence. The classification of breast cancers according to both MRP-1/CD9 and KAI-1/CD82 gene expression will prove to be useful for the clinical treatment of breast cancers patients.
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Acknowledgements |
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Footnotes |
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Supported in part by Grants-in-Aid from the Ministry of Education, Science and Culture of Japan (No 07557253 and 08407040) to M. Miyake.
Accepted for publication June 3, 1998.
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4ß1 (CD49d/CD29). J Immunol 1996, 157:2039-2047[Abstract]
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