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Immunology |
Department of Pathology, Cornell University Medical College, New York, New York 10021 [D. J., Y-T. C.]; Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [E. S., A. O. G., M. J. S., L. J. O.]; and Medizinische Klinik, Hämatologie-Onkologie, Krankenhaus Nordwest, 60488 Frankfurt, Germany [D. J., E. J., A. K.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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One major challenge confronting the analysis of autologous immune responses in breast cancer, however, is the well-recognized difficulty of establishing breast cancer cell lines as targets for immunological analysis. This is in contrast to the relative ease of establishing lines from melanoma, renal cancer, and other tumor types. For this reason, the analysis of the human immune responses against melanoma and the molecular identification of the antigens eliciting these responses (17, 18, 19) are far more advanced in melanoma than in breast cancer.
The recent development of a general method to analyze the humoral immune response of cancer patients that does not require tumor cell lines provides a powerful new way to dissect the immune response to breast cancer. This approach is called SEREX3 (20) . It has now been applied to a wide range of different tumor types (21 , 22) . In the present study, we applied SEREX analysis to breast cancer and have identified a panel of antigens through autologous and allogeneic screening, including two previously isolated CT antigens, NY-ESO-1 (23) and SSX2 (24) , and ING1, a tumor suppressor gene suggested to be involved in breast cancer (25) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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RNA Extraction and Construction of cDNA Expression Library.
Total RNA was extracted from the BR11 tumor sample by the conventional CsCl-guanidine thiocyanate gradient method (28)
. A cDNA library was constructed in a 
-ZAP Express vector, using a commercial cDNA library kit (Stratagene).
Immunoscreening of the cDNA Library.
The BR11 cDNA expression library was amplified once and screened with the autologous patient serum at 1:200 dilution or, alternatively, with an allogeneic pooled serum sample derived from seven different breast cancer patients, at a final dilution of 1:1000 for each serum. The screening procedure was as described previously (20
, 23) . Briefly, the serum was diluted 1:10, preabsorbed with transfected Escherichia coli lysate, further diluted to 1:200 (autologous screening) or 1:1000 dilution (allogeneic screening), and incubated overnight at room temperature with the nitrocellulose membranes containing the phage plaques at a density of 4000–5000 pfu per 130-mm plate. After washing, the filters were incubated with alkaline phosphatase-conjugated goat antihuman Fc
secondary antibodies, and the reactive phage plaques were visualized by incubating with 5-bromo-4-chloro-3-indolyl-phosphate and nitroblue tetrazolium. In addition to the BR11 cDNA library, a commercially obtained testicular cDNA library (Clontech) was also screened with the BR11 serum in an identical fashion.
Sequence Analysis of the Reactive Clones.
The reactive clones were subcloned, purified, and in vivo excised to pBK-CMV plasmid forms (Stratagene). Plasmid DNA was prepared by using the Wizard Miniprep DNA Purification System (Promega). The inserted DNA was evaluated by EcoRI-XbaI restriction mapping, and clones representing different cDNA inserts were sequenced. The sequencing reactions were performed by the DNA Sequencing Service at Cornell University (Ithaca, NY) using Applied Biosystems PRISM (Perkin-Elmer) automated sequencers. DNA and amino acid sequences were compared with sequences in the GenBank and the EST databases using the BLAST program. Genes identical to entries in GenBank were classified as known genes, whereas those that shared sequence identity only to ESTs and those that have no identity in both GenBank and EST databases were designated as unknown genes.
RT-PCR.
To evaluate the mRNA expression pattern of the cloned cDNA in normal and malignant tissues, gene-specific oligonucleotide primers were designed to amplify cDNA segments of 300–600 bp in length, with the estimated primer melting temperature in the range of 65–70°C. For evaluation of CT antigen expression in the tumor tissue, primers specific for MAGE-1, MAGE-2, MAGE-3, MAGE-4, BAGE, NY-ESO-1, SSX1, SSX2, SSX4, SSX5, and SCP1 were prepared following previously used primer sequences (23
, 29, 30, 31)
, or designed based on published sequences (32
, 33)
. All primers were synthesized commercially (Operon Technologies, Alameda, CA). RT-PCR was performed by using 35 amplification cycles in a thermal cycler (Perkin-Elmer) at an annealing temperature of 60°C, and the products were analyzed by 1.5% gel electrophoresis and ethidium bromide visualization.
ELISA against Recombinant Tumor Antigens.
ELISA tests were used to evaluate seroreactivity of patient sera against defined tumor antigens. The preparation of recombinant tumor antigens and the ELISA analysis were performed as described previously (34)
.
RACE.
RACE reactions (5'-RACE) were performed using gene-specific and adaptor-specific primers in conjunction with Marathon-Ready normal testis cDNA and AmpliTaq Gold Polymerase (Perkin-Elmer). Products were ligated into the PCR-direct cloning vector pGEMT plasmid and analyzed by restriction mapping and sequencing.
Genomic Southern Blot Analysis.
Genomic DNA was extracted from normal human tissue. After restriction enzyme digestion, the DNA was separated on a 0.7% agarose gel, blotted onto nitrocellulose filters, and hybridized to a 32P-labeled DNA probe at a high stringency condition (65°C, aqueous buffer). After overnight hybridization, the filters were washed at high stringency condition and exposed for autoradiography.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Non-CT Genes.
In addition to CT antigen genes, 14 distinct gene products (11 known and 3 unknown genes) were identified in the remaining 23 clones. All known genes were widely expressed in normal tissues, demonstrated by the existence of multiple EST entries from normal somatic tissues in the EST database. Of the three unknown genes, two shared identical sequences to ESTs derived from various normal tissues. Gene-specific primers were designed to evaluate the third unknown gene because no EST sequences were found in the database. Results showed universal expression in all normal tissues tested (brain, kidney, liver, colon, and testis). With the exception of ING1, a gene previously implicated as a tumor suppressor gene in breast cancer (25)
, none of the other 13 genes were further investigated.
Allogeneic Screening of BR11 cDNA Library.
A total of 8 x 105 pfu from the BR11 cDNA library was then screened using a pooled serum sample derived from seven different breast cancer patients at a final dilution of 1:1000 for each serum. Twenty-three positive clones were isolated, derived from nine known genes (Table 2)
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Comparison of the genes identified in autologous and allogeneic screening showed that NY-ESO-1 and human keratin 10 gene were the only two genes isolated in both analyses. Some other genes identified in the autologous or allogeneic screening were isolated previously by SEREX, including aldolase A from a lung cancer library (35) , U1snRNP from esophageal (23) and colon cancer libraries (36) , poly(ADP-ribose) polymerase and adenylosuccinate lyase from colon cancer libraries (36) , and alanyl-t-RNA synthetase from renal cancer libraries.4
Screening of a Testicular Library Using BR11 Serum.
To facilitate the identification of CT genes, the BR11 serum was used to screen a testicular library. A total of 4 x 105 clones was screened at 1:200 serum dilution, and 28 positive clones were identified, corresponding to 8 known and 2 unknown genes (Table 3)
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750 bp; Ref. 23
). A comparison with clones identified by BR11 autologous screening showed two genes isolated from both libraries, i.e., the poly(ADP-ribose) polymerase and the tumor suppressor gene ING1. Poly(ADP-ribose) polymerase has also been identified from other SEREX screening, including colon cancer (36)
. In addition, the gene homologous to TITIN was isolated previously from prostate cancer SEREX.5
All genes, except SSX2, were universally expressed, demonstrated by comparison with EST databanks and/or RT-PCR with gene-specific primers.
ING1 Not Mutated in BR11.
Two clones isolated above were identified as tumor suppressor gene candidate ING1 (37)
, one from the BR11 cDNA library (clone BR11–74d), and the other from the testicular library (clone TB-32). Comparison of the BR11–74d (partial cDNA clone, 878-bp insert) with the published ING1 sequence revealed differences in six residues (positions 818, 836, 855, 861, 866, and 874 of full-length ING1 sequence; see variant A in Fig. 1
). To evaluate whether any of these differences represented mutation in the BR11 tumor sample, a short PCR fragment containing the 6-bp differences was amplified from a panel of allogeneic normal tissue cDNA and subcloned into the PCR-direct cloning vector pGEMT. Sequencing analysis of the subcloned fragment showed DNA sequence identical to the BR11–74d clone in all six bases and different from the sequences deposited in GenBank, ruling out the possibility of a mutation in the BR11 cDNA clone. This conclusion was subsequently confirmed by sequencing the testicular clone TB-32 and by restriction analysis of several different normal tissue ING1 cDNA, using enzymes that would distinguish these sequence differences.
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. All three variants were identical in their sequences 3' to nucleotide 586 (based on nucleotide numbering of A variant; Fig. 1
) but differed in their 5' regions, suggesting the likelihood of alternatively spliced variants involving the same exon-intron junction. Moreover, the original ING1 sequence, published by Garkavtsev et al. (25)
, was also different in this 5' region, representing a fourth variant (variant D; Fig. 1
).
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, encoding polypeptides of 279, 235, and 294 amino acid residues, respectively, with 233 amino acids in the shared 3' region. The amino acid sequences are shown in Fig. 2
. No translational initiation site, however, was identified in the 5' unique sequence of the B variant. To explore the possibility of additional ORFs in the 5' end of variant B transcripts, 5' RACE experiments were performed using variant B specific primers and testicular mRNA as the substrate. Cloning and sequencing of the RACE products revealed the variant C sequence 5' to the original variant B sequence shown in Fig. 1
, and the full-length variant B cDNA contained an additional exon of 609 nucleotides between the variant C sequence and the shared 3' sequence. This additional exon of variant B, however, did not contain any ORF, and the first available initiation site for variant B would be the internal methionine at amino acid position 70 of the predicted ING1 peptide of variant A. If expressed, variant B would thus be a truncated form of the ING1 gene product (210 amino acid residues), with a 5' untranslated region of 681 bp (Fig. 2)
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Tissue-specific Expression of ING1 Transcripts.
The presence of transcript variants, having at least three different transcriptional initiation sites and possibly different promoters, raised the possibility that their mRNA expression is under different tissue-specific regulation. To evaluate this, the expression of variants A, B, and C were analyzed by RT-PCR using variant-specific primers.
Of five normal tissues and cultured melanocytes, only variant A is universally expressed in these tissues and cells. Variant B is expressed in testis, liver, and kidney, weakly expressed in colon and brain, and not expressed in normal breast and cultured melanocytes. Variant C is expressed only in testis and weakly in brain but not in breast, colon, kidney, or melanocytes. Examples of this analysis are shown in Fig. 3
. Expression of these transcripts in tumor tissue and cell lines was then examined. RT-PCR analysis of BR11 tumor RNA, six breast cancer cell lines, and eight melanoma cell lines showed clear expression of variant A in all tumor cell lines. The signal intensity in BR11 is slightly weaker. Four of six breast cancer cell lines weakly expressed variant B, and all eight melanoma cell lines were negative. None of the breast or melanoma cell lines expressed variant C (Fig. 3)
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Cloning of an ING1 Homologue Gene.
Screening the BR11 library using an ING1 cDNA probe derived from clone BR11–74d led to the identification of a novel cDNA (593 bp) with strong homology to the ING1 sequence. Genomic Southern blot analysis using ING1 probe showed two hybridizing DNA species, one of which also hybridized to the 593-bp ING1-like cDNA probe (Fig. 4)
, confirming the presence of two ING1-related genes in human genome. The transcriptional initiation site of this new ING1-like gene was defined by 5' RACE using normal fetus cDNA, and the full-length cDNA is of 771 bp in size excluding the poly(A) tail. This novel gene, designated as ING2, showed strong nucleotide homology to ING1 (Fig. 5)
, with strongest homology in the 5' two-thirds of the sequence (76% identity, nucleotides 1–480). However, the longest ORF in this ING2 gene is only 129 bp in length and would encode a polypeptide of 42 amino acids (Mr 5076), homologous to (76% amino acid identity) but much shorter than the ING1 products (210 amino acids to 294 amino acids for different variants). Excluding this coding region, the ING2 contains 203 bp of 5' untranslated region and 439 bp of 3' untranslated region.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Several categories of antigens have emerged from the SEREX studies to date (22
, 41)
. These include differentiation antigens, mutational antigens, amplified/overexpressed antigens, retroviral antigens, splice variant antigens, and CT antigens. Tyrosinase, a classic example of a differentiation antigen in melanocytes, was recognized by an autologous melanoma patient serum in the initial SEREX analysis (20)
. Mutational antigens recognized by SEREX include mutated p53 in colon cancer (36)
and possibly gene products encoded by chromosome 3p candidate tumor suppressor genes, isolated from lung cancer (35)
and renal cancer (20)
. Overexpressed antigens include aldolase-A (35)
and eIF-4 in lung cancer and carbonic anhydrase XII precursor in renal cancer4. HERV-K10, an endogenous retroviral gene product, is the sole example of viral antigens identified by SEREX (20)
. Several splice-variant antigens have been found by SEREX, including restin from Hodgkin’s disease (20)
and NY-CO-38 from colon cancer (36)
. Given the multiple splicing isoforms of the candidate tumor suppressor gene ING1 identified in the current study, a splice variant of ING1 product may be the immunogenic stimulus leading to antibody formation.
The most frequently isolated genes in the present study are CT antigens, a special class of differentiation antigens. In normal tissues, CT expression is generally restricted to testis. In cancer, CT expression is found in a variable proportion of a wide range of different cancer types. Ten CT antigen genes or gene families have been defined to date: MAGE, BAGE, and GAGE as T-cell reactive tumor antigens (32 , 33 , 42 , 43) ; NY-ESO-1, SSX, SCP1, CT7, and CT8 as SEREX-defined antigens (23 , 24 , 29 , 38) ;7 CT9 as a testis-specific gene,8 and CT10 as a gene identified by representational difference analysis between a melanoma cell line and normal skin.9 Of these, MAGE-1, MAGE-4, NY-ESO-1, SSX2, SCP1, CT7, and CT8 have been found in SEREX (22) . Our isolation of NY-ESO-1 and SSX2 is the first time that these two antigens were isolated from breast cancer by SEREX, indicating that these two antigens, among other CT antigens, may be suitable targets for breast cancer vaccines. This view is further supported by the recent studies demonstrating NY-ESO-1 expression in 24% of breast cancer and SSX (various gene family members) in 23% (41 , 44) .
The major focus of the present study was the ING1 gene, originally isolated by cloning of genes that were preferentially expressed in a normal breast epithelial cell line but not in breast cancer lines. By Western blotting with a polyclonal antibody, the product of the ING1 gene was shown to be a protein of Mr 33,000, designated p33ING1. By soft-agar and focus-forming assays, it has been shown that cells expressing ING1 in an antisense orientation would confer growth advantage (25) . Acute transfection of ING1 sense construct into a breast cancer line led to growth inhibition, supporting the notion that ING1 is a tumor suppressor gene (25) . Subsequent studies showed this gene to be involved in the negative regulation of cell proliferation and in cellular aging and apoptosis (45 , 46) . The ING1 gene is mapped to chromosome 13q34 (47) , one of the regions reported to be affected by loss of heterozygosity in breast cancer (48 , 49) . In a recent study by Garkavtsev et al. (37) , the authors showed that the biological effects of ING1 and p53 are interrelated and require the simultaneous expression of both genes. This interaction was further supported by the physical association between p53 and p33ING1, shown by coimmunoprecipitation experiments using anti-p53 antibodies (37) .
Comparison of the BR11–74d clone sequence with the ING1 sequence in the original cloning paper (Ref. 25 ; GenBank accession number AF001954) showed that BR11–74d is a partial cDNA clone of ING1 but with six scattered single-base differences. Repeated sequencing and restriction analysis of several normal tissues DNA showed no difference between normal ING1 sequence and the BR11–74d sequence, and the sequence in the GenBank entry was not observed. We have thus concluded that these single-base differences represent either sequencing errors in the GenBank entry or the presence of a rare allelic polymorphism.
Analysis of the ING1 cDNA clones from normal testicular library revealed the presence of three variants with different 5' segments (variants A, B, and C), which are all different from the originally cloned ING1 sequence (variant D; GenBank AF001954). Further comparison showed variant A to be identical to a more recent entry of ING1 sequence in GenBank submitted by the original ING1 cloning group (accession number AF044076). Review of the published p33ING1 studies (25 , 37 , 45, 46, 47 , 50) , however, found no mentioning of the variant A sequence, and it is unclear whether the p33ING1 protein identified by anti-p33ING1 polyclonal antibody (and the p33ING1 coprecipitated by anti-p53 antibody) represented the product of variant A, variant D, or more than one variant. Because these four ING1 protein variants would have predicted molecular masses ranging from 24 to 33 kD, the fact that p53 antibody appeared to coprecipitate one single species of p33 would suggest that only one of the variants is involved in this p53-ING1 interaction. Direct sequencing of the p53-interacting ING1 species may thus help to clarify the biological roles of these variants and provide insight into the functional significance of their tissue-specific expression. In addition, by using these cDNA variants in the transfection-type experiments originally used to define the tumor-suppressive nature of the ING1 gene, the functional properties of these variants could be explored, e.g., their relative strength in growth inhibition of cell lines. Similarly, it would be intriguing to transfect the newly isolated ING2 gene in this assay system to determine whether ING1 and ING2 elicit same or different biological effects.
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FOOTNOTES |
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1 This work was partially supported by NIH Grant CA-68024 and by the Cancer Research Institute/Rhea (Rose Marie) Finnell Memorial Fellowship. 
2 To whom requests for reprints should be addressed, at Department of Pathology, Cornell University Medical Center, 1300 York Avenue, New York, NY 10021. Phone: (212) 746-6472; Fax: (212) 746-4483; E-mail: ytchen{at}mail.med.cornell.edu
3 The abbreviations used are: SEREX, serological analysis of recombinant tumor cDNA expression libraries; pfu, plaque-forming unit(s); CT, cancer-testis; RT-PCR, reverse transcription-PCR; RACE, rapid amplification of cDNA ends; EST, expressed sequence tag; ORF, open reading frame.
4 M. J. Scanlan, personal communication.
5 Y. Obata, personal communication.
6 Internet address: http://www.licr.org/SEREX.html.
7 Ö. Türeci and U. Sahin, personal communication.
8 M. J. Scanlan, personal communication.
9 A. O. üre, personal communication.
Received 5/27/99. Accepted 10/18/99.
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