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Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33101 Tampere, Finland [M. B.]; Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892-4470 [O. M., J. K., R. C., O-P. K., A. K.]; and Institute of Pathology, University of Basel, CH-4003 Basel, Switzerland [J. T., G. S.]
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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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Materials and Methods |
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Primary Tumors.
A total of 372 ethanol-fixed primary breast cancers were obtained from
the Institute of Pathology, University of Basel (Basel, Switzerland).
The tumor samples were reviewed by one pathologist (J. T.) and
included 69.6% ductal carcinomas, 14% lobular carcinomas, 2.4%
medullary carcinomas, 1.6% mucinous carcinomas, 0.8% cribriform
carcinomas, 0.8% tubular carcinomas, 0.5% papillary carcinomas, 4%
ductal carcinomas in situ, and 6.1% of other rare
histological subtypes or unclassified carcinomas. The grade
distribution was 24% grade 1, 40% grade 2, and 36% grade 3. The pT
stage was pT1 in 29% of patients, pT2 in 54% of patients, pT3 in 9%
of patients, and pT4 in 8% of patients. The average age of the
patients was 60 years (range, 28–92 years); 45% of patients had
node-negative disease, and 55% of patients had node-positive disease.
All specimens evaluated were anonymous, archival tissue specimens. The
use of these tissue specimens in retrospective analyses was approved by
the Ethics Committee of the University of Basel on November 4, 1997,
and the use of such specimens for tissue microarray analysis was
approved by the NIH Institutional Review Board (exemption day, March 4,
1998).
Tissue Microarray Construction.
The tissue microarrays were constructed as described previously
(5)
. Briefly, a representative tumor area was marked from
H&E-stained sections of each tumor. The blocks and the corresponding
histological slides were overlayed for tissue microarray sampling. A
tissue microarray instrument (Beecher Instruments, Silver Spring, MD)
was used to create holes in a recipient paraffin block, to obtain
cylindrical tissue biopsies with a diameter of 0.6 mm from the donor
paraffin blocks, and to transfer these biopsies to the recipient block
at defined array positions. Multiple 5-µm sections were cut from the
tissue microarray block using a microtome with an adhesive-coated
tape sectioning system (Instrumedics, Hackensack, NJ).
Physical Mapping.
RAD51C, S6K, SIGMA1B, PAT1,
NACA, and TBX2 were mapped against a panel of
Centre d’Etude du Polymorphisme Humain YACs by PCR. The PCR primer
sequences were obtained from the Unigene
database.6
The chromosomal localization of the YACs was verified by FISH to normal
metaphase chromosomes.
DNA Probes for FISH.
Gene-specific BAC clones were obtained by screening a human BAC library
(Genome Systems, St. Louis, MO) using PCR with gene-specific primers.
BAC probes were labeled with SpectrumOrange using random priming.
SpectrumGreen-labeled chromosome 17 centromere probe (Vysis Inc.) was
used as a reference.
Copy Number Analysis by FISH.
Interphase FISH to breast cancer cell lines was done as described
previously (3)
. The hybridizations were evaluated using a
Zeiss fluorescence microscope, and approximately 20 nonoverlapping
nuclei with intact morphology based on the
4',6-diamidino-2-phenylindole counterstain were scored to determine the
mean number of hybridization signals for each test and reference probe.
For the tissue microarrays, FISH was performed as described previously
(5)
. Briefly, consecutive sections of the array were
deparaffinized, dehydrated in ethanol, denatured at 74°C for 5 min in
70% formamide/2x SSC, and hybridized with test and reference probes.
The specimens containing tight clusters of signals or a >3-fold
increase in the number of test probe signals as compared with the
chromosome 17 centromere signals in at least 10% of the tumor cells
were considered as amplified.
Northern Hybridization.
Total RNA was extracted from breast cancer cell lines, and the Northern
hybridization was performed using standard methods. Briefly, 10 µg of
total RNA were transferred on a Nytran membrane (Schleicher & Schuell,
Keene, NH). The blot was prehybridized for 1 h at 68°C in
Express Hybridization solution (Clontech, Palo Alto, CA) together with
boiled sheared DNA (10 µg/ml; Research Genetics, Huntsville, AL). PCR
products or sequence-verified cDNA inserts were labeled with
32P by random priming (Prime-It; Stratagene, La
Jolla, CA). Hybridization was performed in the prehybridization
solution at 68°C overnight. The membrane was washed several times
with 2x SSC/0.05% SDS at 30°C and then washed in 0.1x SSC/0.1%
SDS at 50°C. Hybridized probe was detected autoradiographically or by
using a Molecular Dynamics PhosphorImager. After removal of the bound
probe, the membrane was rehybridized with glyceraldehyde-3-phosphate
dehydrogenase probe to confirm equal loading among samples.
Expression Analyses in Primary Breast Tumors.
Total RNA was extracted from 12 primary breast tumors using the RNeasy
kit (Qiagen, Inc., Valencia, CA). The PCR analyses were performed using
the LightCycler system (Roche Diagnostics Corp., Indianapolis, IN).
Briefly, PCR was performed using 2 µl of LightCycler RT-PCR Reaction
Mix SYBR Green I, 0.5 µM of each of the 3' and 5'
primers, 0.4 µl of LightCycler RT-PCR Enzyme Mix, 500 ng of RNA, and
H2O to a final volume of 20 µl. The
MgCl2 concentration was optimized separately for
each primer set and was 5 mM for S6K, 6 mM for
PAT1, and 7 mM for RAD51C and TBX2. Assays were performed
using total RNA from MCF-7 and HBL-100 breast cancer cell lines as
positive and negative controls, respectively. Reverse transcription was
done at 55°C for 10 min followed by inactivation at 95°C for
30 s. Amplification was done in three steps (denaturation at
95°C for 1 s with a temperature transition rate of
20°C/s, annealing at 58°C for 10 s with a temperature
transition rate of 20°C/s, and extension at 72°C for 10 s
with a temperature transition rate of 20°C/s) for 45 cycles. Melting
curve analysis was performed to discriminate between nonspecific and
specific products. The PCR products were denatured at 95°C for 0 s, and then the temperature was dropped quickly to 58°C for 20 s
and raised slowly to 90°C at 0.2°C/s. The amount of the SYBR Green
fluorescence was measured simultaneously and reflects the amount of
double-stranded DNA. The rate of fluorescence change (-dF/dT) was
plotted as a function of temperature.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Copy number changes of RAD51C, S6K,
SIGMA1B, PAT1, NACA, and
TBX2 were studied by FISH in seven breast cancer cell lines.
Four cell lines (BT-474, KPL-1, MCF-7, and ZR-75-1wt) were previously
known to have amplification or gain at 17q22-q24 by CGH, whereas three
cell lines (SUM-52, HBL-100, and MDA-436) did not show any copy number
increase at this region (3
, 6)
. All six genes were found
to be highly amplified (8–19-fold relative to the chromosome 17
centromere) in three cell lines (KPL-1, MCF-7, and ZR-75-1wt; Table 1
; Fig. 1
). In addition, 4–5-fold amplification of S6K,
SIGMA1B, and PAT1 was seen in BT-474, and
4–5-fold amplification of NACA and TBX2 was seen
in SUM-52 (Table 1)
.
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. NACA was ubiquitously expressed in all cell lines, and
SIGMA1B showed elevated expression only in BT-474 and
HBL-100, indicating that the expression of these two genes did not
correlate with amplification levels. The expression of
RAD51C, S6K, and PAT1 was elevated in
all cell lines with amplification (Fig. 2)
. Interestingly,
RAD51C was also overexpressed in BT-474, which did not show
amplification of this gene. TBX2 was expressed in the three
cell lines with high-level amplification but was not detectable in the
SUM-52 cell line, which had low-level amplification.
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. Thirty-nine tumors (10.5%) showed amplification of at least one of
the genes. RAD51C was amplified most infrequently (in 3.1%
of cases), and it was always coamplified with the other three genes.
S6K amplification was seen in 10.2% of the tumors,
PAT1 amplification was seen in 8.9% of the tumors, and
TBX2 amplification was seen in 8.6% of the tumors. In a
majority of the cases (62%), S6K, PAT1, and
TBX2 were amplified simultaneously. However, amplification
of a single gene was observed in 12 tumors (31%) [S6K in 5
tumors, PAT1 in 4 tumors, and TBX2 in 3 tumors].
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. RAD51C was expressed in all four cases with
RAD51C amplification and was also expressed in two of eight
tumors without amplification. Similarly, S6K was
consistently expressed in all nine tumors with S6K
amplification and in one of three tumors without amplification.
PAT1 was expressed in five of eight amplified tumors, and
TBX2 was expressed in three of eight amplified tumors and in
none of the four nonamplified primary breast cancers.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Using the high-throughput tissue microarray technology, we examined the involvement of RAD51C, S6K, PAT1, and TBX2 in a large set of primary breast tumors. Analysis of amplifications of these four genes in the series of 372 primary tumors could be accomplished in just four consecutive FISH experiments (resulting in about 1500 observations). Amplifications of S6K, PAT1, and TBX2 were seen in about 10% of the tumors, whereas RAD51C was clearly less frequently amplified. Although S6K, PAT1, and TBX2 were occasionally found to be independently amplified, coamplification of S6K, PAT1, and TBX2 was the predominant pattern in up to 62% of the tumors. It is unclear whether S6K, PAT1, and TBX2 are part of a single amplicon or whether they represent separate amplicons at 17q23. However, considering the relatively small distance of these genes from one another, we believe that in most cases they are located on a single amplicon. Similar coamplifications have been reported previously in breast cancer. For example, multiple putative target genes, such as EMS1 and CCND1, have been identified at 11q13, and target genes BTAK, ZNF217, and NABC have been identified at 20q13 (7 , 8) .
Although RAD51C was amplified less often in primary tumors than the other genes, it was clearly overexpressed in all cell lines and primary tumors with amplification and also in one cell line (BT-474) and two primary breast tumors without amplification. Thus, overexpression of RAD51C could play a role in breast cancer development and progression. RAD51C is the sixth member of the RecA/RAD51 gene family that encodes strand-transfer proteins involved in both recombinational repair of DNA damage and meiotic recombination (9) . RAD51 protein interacts with the tumor suppressor protein TP53 (p53) as well as with the breast cancer susceptibility gene (BRCA1 and BRCA2) products (10 , 11) . RAD51C shows a 27% sequence identity to RAD51, and the homology is at the region of the protein that is involved in the protein-protein interaction (9) . It is thus possible that RAD51C also interacts with p53 and BRCA1/BRCA2, making it an interesting candidate for an amplification target gene. Such interactions between oncogenes and tumor suppressor genes, e.g., MDM2 and p53 as well as MYC and BRCA1, have been previously implicated to play a role in human cancer (12 , 13) .
PAT1 and TBX2 were shown to be more frequently amplified in primary breast tumors than RAD51C, but they were not consistently expressed in all cases with amplification. However, the fact that they were sometimes expressed in 17q23-amplified primary breast cancers suggests that they may modify the phenotype of these tumors. PAT1 (also known as APPBP2) is a cytoplasmic protein that is involved in the translocation of amyloid precursor protein along microtubules toward the cell surface (14) and has not been previously linked to cancer. TBX2 is a member of a gene family of transcription factors named T-box genes (15) . Members of the T-box gene family play important roles in developmental gene regulation. TBX2 is normally expressed in the milk ridge, thickened ridge of underlying mesenchyme during the development of the duct system of the mammary gland in mouse (16) and could therefore play a role in breast cancer by mediating mesenchymal/epithelial cell interactions.
Of the four genes identified in this study, the ribosomal protein S6 kinase (S6K) has been previously implicated in breast cancer (17 , 18) . S6K was most frequently amplified in primary breast tumors and was expressed in all cases with amplification as well as in one tumor without amplification. S6K encodes for a critical mediator involved in G1 to S-phase progression and is possibly also involved in the control of cell size (19 , 20) . Therefore, based on its biological role, it also represents an ideal candidate for an amplification target gene. Furthermore, we recently showed using another set of tumors with clinical follow-up information that amplification and overexpression of S6K are associated with poor prognosis of the patients independently of HER-2 amplification at 17q12 (18) .
In summary, our findings indicate that the frequent amplification of 17q23 in breast cancer leads to up-regulation of at least four genes, RAD51C, S6K, PAT1, and TBX2, suggesting that their simultaneous activation may contribute to the genesis and the progression of breast cancer. Further functional analyses of the genes reported here will have to be undertaken to define which of them play the most important roles in breast cancer progression. Based on the Human Gene Map,4 the 17q23 region is a relatively gene-rich region of the genome. Thus, it is possible and even likely that other genes mapping to this region will also be affected by the amplification. Therefore, we are currently undertaking a full expression survey of all transcripts from the 17q23 amplicon (altogether, about 200 clones) using cDNA microarray technologies to further evaluate the hypothesis that multiple genes in DNA amplicons play important roles in cancer progression.
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ACKNOWLEDGMENTS |
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Note Added in Proof: We recently cloned a genomic rearrangement with the exact same
breakpoint in the MCF7, KPL-1, and ZR-75-1wt cell lines indicating that
these cell lines may be clonal variants of one another. Genotyping with
highly polymorphic markers showed that KPL-1 and ZR-75-1wt are both
likely to have derived from the MCF7 cell line. Despite this clonal
relationship, the three cell lines do possess unique characteristics,
such as several distinct genetic alterations by CGH and a variable gene
expression pattern by cDNA microarray analysis. The Northern analysis
shown in Fig. 2
also illustrates that these three cell lines
(Lanes 1–3) are not exactly identical. In this study, the
results obtained from cell lines were extensively validated in
vivo in uncultured tumors, and, therefore, this new information
does not impact the conclusions of our study. However, these findings
further emphasize the critical need for technologies and strategies
utilized in this study: validation of genes discovered from model
systems in vivo using tissue microarrays.
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FOOTNOTES |
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1 Supported in part by grants from The Research
and Science Foundation of Farmos, the Medical Research Fund of Tampere
University Hospital, The Finnish Medical Foundation, The Irja Karvonen
Cancer Foundation, and the Swiss National Science Foundation (Grant
81BS-052807). 
2 To whom requests for reprints should be
addressed, at Cancer Genetics Branch, National Human Genome Research
Institute, NIH, 49 Convent Drive, Room 4B24, Bethesda, MD 20892-4470.
Phone: (301) 402-6048; Fax: (301) 402-7957; E-mail: akallion{at}nhgri.nih.gov
3 The abbreviations used are: CGH, comparative
genomic hybridization; FISH, fluorescence in situ
hybridization; BAC, bacterial artificial chromosome; YAC, yeast
artificial chromosome; RT-PCR, reverse transcription-PCR.
4 World Wide Web address:
http://www.ncbi.nlm.nih.gov/genemap/.
6 World Wide Web address:
http://www.ncbi.nlm.nih.gov/UniGene/.
7 World Wide Web address:
http://www-genome.wi.mit.edu/.
Received 10/28/99. Accepted 8/15/00.
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