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Virology |
Departments of Medicine [B. L., Y. W., S. M. M., I. P., V. N., J. F. H.] and Microbiology [B. G-T. P.], Mount Sinai School of Medicine, New York, New York 10029
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ABSTRACT |
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In this article we report the amplification of a whole proviral structure from each of two human breast carcinomas that were env positive. Using nested extra-long PCR and primers from specific MMTV sequences, overlapping env-long terminal repeat (LTR), LTR-gag, gag-pol, and pol-env segments were successfully amplified. The 9.9-kb provirus is 95% homologous to MMTV but only 57% to human endogenous retrovirus K10 in 3.5 kb of the gag and pol genes. The provirus displays typical features of a replication competent virus, plus the open reading frame for the superantigen and the glucocorticoid responsive element. Fluorescence in situ hybridization with a 2.7-kb env-LTR sequence of an env-positive breast cancer cell line revealed that the sequence is inserted in several chromosomes but not in chromosomes from normal breast cells.
The origin of the MMTV-like sequences is uncertain. Because they are undetectable in normal tissues, because the similarity between the two isolates is high (96%), and because they maintain open reading frames, they appear to be exogenous.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In an effort to exclude confusion with known endogenous retroviruses, we selected a 660-bp region of the MMTV env gene that has low homology to HERV-K10, the prototype human retrovirus most similar to MMTV (4) , designed primers to this env gene region, and used the PCR to detect the 660-bp sequence. We found this specific env gene sequence in 38% of unselected breast cancers of American women. The sequence was rarely present (2%) in normal breasts but was not found in other tumors or tissues (5) . The sequence was detected by Southern blot hybridization under stringent conditions. Similar results have been reported recently by Etkind et al. (6) . We have also shown that this sequence is expressed in 66% of the sequence-positive tumors and in some breast cancer cell lines (7) . These observations also suggested that the sequence was present in a very low copy number. When the phenotypic characterization of tumors containing the sequence was studied, a correlation was found between env-positive tumors and expression of laminin receptor (8) , a characteristic parameter of breast cancer aggressiveness (9) . In addition to the env sequences, we have reported the detection of MMTV-like LTR sequences in human breast cancers that were env sequence positive. A 1.6-kb env-LTR sequence was also found that provided evidence that there was continuity between the two genes.4
We set out to establish if other retroviral genes homologous to MMTV are present in env gene-positive human breast cancers and, if so, whether they are distinct from the known endogenous proviruses, which are defective. We have now amplified, cloned, and sequenced a series of overlapping fragments that correspond to a 9.9-kb proviral sequence from each of two human breast cancers. Characterization of this entire sequence indicated that it is highly homologous to MMTV but not to HERV-K10 and that it has potentiality for replication.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Breast carcinomas and tissue from reduction mammoplasties of normal breasts were harvested fresh, and aliquots discarded by pathologists were transported on ice and frozen at -70°C until used. The protocol for these studies was approved by the Institutional Review Board. DNA was extracted from tumors and tested for env sequences as previously described (5) . To determine whether the DNA could be amplified in large sequences, a 2,150-bp segment of the ß-actin gene was first amplified with XL-PCR, using rTth DNA polymerase (Perkin-Elmer), under the conditions recommended by the manufacturer. Primers used were as follows: actin 1, 5' TCC GAC CAG TGT TTG CCT TTT ATG 3' (positions 921 to 944); actin 2, 5' ACT GCT GTC ACC TTC ACC CTTC 3' (positions 3150 to 3171). The 100-µl reaction mixture containing 2 units of enzyme, 10 µl 10x buffer provided by the manufacturer, 1 µg DNA, 20 ng of each primer, 200 µM of each nucleotide, and 1 mM Mg acetate was incubated at 93°C for 1 min for 1 cycle, then for 16 cycles at 93°C for 1 min and 68°C for 10 min, followed by 93°C for 1 min and 68°C for 10 min, increasing 15 s each cycle for 12 cycles, and then at 72°C for 10 min ending at 4°C.
Amplification Cloning and Sequencing of 2.7-kb
env-LTR Sequence.
Two rounds of XL-PCR were performed to amplify a 2.7-kb
env-LTR sequence. Primers 5L and LTR3 were used for both
rounds. The product of the reaction was detected in 1% agarose gel
electrophoresis and by Southern blot hybridization with an internal
sequence (LTR5) that was end-labeled with
[
-32P]ATP (NEN, Boston, MA) using the T4
polynucleotide kinase (New England Biolabs). The radiolabeled
oligonucleotide was purified using a TE MIDI select G-25 column (5
Prime 
3 Prime, Boulder, CO) following the protocol provided by the
manufacturer. Hybridization was carried out as described previously
(5
, 7)
. The same strategy was used to amplify and sequence
the 2.7-kb env-LTR fragment from tumors MSSM 1 and MSSM 2.
Amplification and Cloning of 1.3-kb LTR-gag
Sequence.
Primers LTR5 and GAG4 were used to amplify a 1.58-kb LTR-gag
sequence. Nested PCR with primers LTR5 and GAG3 was then performed,
using AmpliTaq polymerase following conditions recommended by the
supplier (Perkin-Elmer) to amplify 1.3 kb. Perfect-match PCR
Enhancer (Stratagene) was used to increase product specificity.
Thermocycling conditions were as follows: 1 cycle of 94°C for 2 min,
followed by 30 cycles of 94°C for 1 min, 55°C for 1 min, and 70°C
for 2 min and by 1 cycle of 72°C for 10 min. The 1.3-kb PCR product
was electrophoresed in 0.8% agarose gel followed by Southern blot
hybridization with labeled LTR3. The 1.3-kb sequence was cloned and
sequenced. An additional 265-bp sequence in the gag gene was
amplified with primers GAG3R and GAG4 and directly sequenced from the
PCR product. The same strategy was used to amplify 1.3-kb
LTR-gag fragment from tumors MSSM 1 and MSSM 2.
Amplification and Cloning of a 0.8-kb pol-env
Sequence.
Conditions for PCR were the same as for amplification of
LTR-gag. The first-round PCR was performed with primers
GAG4R and EPR and nested PCR with primers POL3'R and 5LR. The 0.8-kb
PCR product was electrophoresed in 2% agarose gel, and Southern
hybridization with labeled ENV1 was performed. The same strategy was
used to amplify the 0.8-kb pol-env junction from tumor MSSM
1 and MSSM 2.
Amplification and Cloning of a 2.2-kb 5' gag-pol
Sequence from Tumor MSSM 1.
The same XL-PCR conditions as above were used. Primers GAG4R and EPR
were used for the first-round of PCR, followed by nested PCR with
primers GAG4R and POL5R. A 2.2-kb fragment was electrophoresed, and
Southern hybridization with labeled POL4 was performed.
Amplification and Cloning of a 3.09-kb 3' gag-pol
Sequence from Tumor MSSM 1.
The XL-PCR conditions described above were used to amplify a 3.09-kb
viral sequence. The first-round PCR was performed with primers GAG4R
and EPR followed by nested PCR with primers GAG7 and POL1.
Perfect-match PCR Enhancer (Stratagene) was added to the PCR reaction.
Thermocycling conditions were as follows: 93°C for 1 min for 1 cycle
and then 25 cycles of 93°C for 1 min, 55°C for 1 min, 68°C for 10
min, and 1 cycle at 72°C for 10 min. The 3.09-kb PCR product was
electrophoresed in 1% agarose gel, followed by Southern hybridization
with labeled POL5. An additional 380-bp sequence between pol
and env genes was amplified with primers POL1R and POL3'R,
hybridized with labeled POL9, and sequenced directly from the PCR
product.
Amplification of Sequences from Tumor MSSM 2.
A different strategy was used to amplify and clone some of the
sequences from the second tumor. The same primers and PCR conditions
were used to clone the 2.7-kb env-LTR, 1.3-kb
LTR-gag, and 0.8-kb pol-env fragments. However,
the gag-pol region was amplified with primers GAG2 and POL8R
for the first-round PCR and with primers GAG3R and POL8R for the
next-round PCR, and Southern blot hybridization was performed with
labeled probe POL4. The pol-env region was amplified with
primers POL8 and 3L for the first-round PCR and then with primers POL8
and ENV5R for the second-round PCR. The same PCR conditions were used
as described for amplification of pol-env sequences. The
amplified PCR products were separated by 2% agarose gel
electrophoresis, and Southern hybridization with labeled POL5 was
carried out as above.
Cloning and Sequencing of the Amplified Sequences.
The PCR products were ligated into the pCR II vector from Original TA
Cloning Kit (Invitrogen, San Diego, CA) and grown in INV
F' One shot
competent cells (Invitrogen). White colonies were selected, and
isolation and purification of the plasmids were accomplished using
Plasmid Maxi Kit (Qiagen, Chatsworth, CA). EcoRI digestion
and 1% agarose gel electrophoresis and Southern blot hybridization
with labeled probes were performed to test for the presence of cloned
inserts, and finally, the purified DNA was sequenced by automated DNA
sequencing. The sequences were then compared with known sequences of
MMTV, HERV-K10, and others through the GenBank program.
FISH.
The 2.7-kb env-LTR fragment was used as a probe after
nick-translation with dioxigenin (Boehringer Mannheim). The conditions
described by Najfeld et al. (11)
were used for
hybridization and detection.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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together with their location in the MMTV genome
(12)
. All PCRs were performed with tumor and normal breast
DNAs. Only the amplified fragments for tumor DNA are shown, because
normal DNA failed to be amplified with these primers.
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, the position of the primers is indicated, and in Fig. 1B
, the product of two rounds of XL-PCR using primers 5L and
LTR3 is shown as well as Southern blot hybridization with probe LTR5.
The results of sequencing and comparison to MMTV strain BR6 and to
endogenous HERV-K10 are summarized in Fig. 1A
. The 2.7-kb
sequence was 94 and 95% homologous to MMTV in 2.59 kb of the two
breast cancers but only 55 and 64% homologous to HERV-K10 in 116 bp
(GenBank accession number AF243039).
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, the position of the primers is indicated, and in Fig. 2B
, the product of nested PCR with primers LTR5 and GAG4,
followed by PCR with primers LTR5 and GAG3, is shown as well as
Southern blot hybridization with probe LTR3. The 1.3-kb sequence from
the two tumors showed 94% homology to MMTV in 1.3-kb and 66 to 67%
homology to HERV-K10 in 179 bp (Fig. 2A
; GenBank Accession
number AF248271).
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, the position of the primers is indicated, and in Fig. 3
B, the product of nested XL-PCR with primers GAG4R and EPR,
followed by PCR with primers GAG4R and POL5R, is shown as well as
Southern blot hybridization with probe POL4. The 2.2-kb sequence from
the two tumors was 94 to 95% homologous to MMTV over its entire length
but only 59% homologous to HERV-K10 in 118 bp (Fig. 3A)
.
The 2.2-kb sequence contains the ORFs for the dUTPase and the protease
(prt) genes (GenBank accession number AF248272).
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, the position of the primers is indicated, and in Fig. 4
B, the product of nested XL-PCR with primers GAG4R and EPR,
followed by PCR with primers GAG7 and POL1, is shown as well as
Southern blot hybridization with POL5. The 3.09-kb sequence from the
two tumors was 95% homologous to MMTV in 3.02 kb and 69 to 70%
homologous to HERV-K10 in 160 bp (Fig. 4A
; GenBank accession
numberAF248269).
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, the position of the primers is indicated, and in Fig. 5B
, the product of the XL-PCR with GAG4R and EPR, followed
by PCR with primers POL3'R and 5LR, is shown as well as Southern blot
hybridization with probe ENV1. The 0.8-kb sequence from the two tumors
was 94 and 95% homologous to MMTV in 745 bp and 60% to HERV-K10 in 25
bp (Fig. 5A
; GenBank Accession number AF248270).
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. Total homology from the two carcinomas was 95% to MMTV in 9.9 kb and
57% to HERV-K10 in 3.5 kb. Homology to the endogenous retrovirus was
seen primarily in the pol gene, which is known to be
conserved among different retroviruses and partially in the
gag gene. Similarity between the two tumors was 96%,
indicating that they were closely related but not identical. The
differences were randomly distributed across the provirus genome.
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shows one metaphase with hybridization signals produced by the 2.7-kb
env-LTR sequence on four chromosomes.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The strategy followed for detecting the proviral sequences was the use of primers with low homology to known genes and viral endogenous sequences, followed by amplification of sequences of contiguous genes using the putative primers from the known sequences (chromosome walking).
Analysis of the proviral sequences demonstrates that they have
potential for expression and replication. The LTRs contain all of the
enhancer and promoter elements characteristic of a replication
competent MMTV-like virus as well as the glucocorticoid responsive
element and the superantigen sequences. The other genes did not show
evidences of deletions or early stop codons as do
replication-incompetent endogenous retroviruses (13)
. The
gag gene contains the dUTPase and prt ORFs (Fig. 6)
.
The putative HMTV overall homology to MMTV is 95% in both isolates. However, when 14 cloned MMTV-like env human sequences were compared with MMTV strains, the homology varied from 84 to 99%, suggesting that they are homologous to but not identical with MMTV (14) . Furthermore, sequencing of 10 LTR human isolates revealed that there are certain specific deletions and insertions at the COOH-terminal of the superantigen sequences that clearly differentiate them from the MMTV strains.5
Comparison of the two isolates with the HERV-K10, the endogenous retrovirus closely related to MMTV (4 , 15) , revealed 57% homology in 3.5 kb of the pol and prt genes. Endogenous retroviruses contain deletions and early stop codons in different genes that make them replication incompetent. This is not the case of the two HMTV isolates.
The HERV-K family, which accounts for 1% of the human genome, is expressed to different degrees among individuals and cell types (16) . HERV-K10 is expressed in some teratocarcinoma cell lines (13) . One of these defective proviral elements, the HML6 BC1, was found to be expressed in only 1 breast carcinoma of 60 examined (17) . Yin et al. (17) concluded that the role of their element in breast cancer remains unclear.
The origin of the proviral sequences that we have detected only in breast carcinomas is not yet established. Their absence from normal breast samples (2%) and from other tissues of the same patients whose tumors contain the sequences (5) suggests an exogenous origin. The possibility that they are endogenous and detectable only in tumors because of aneuploidy is improbable, because many aneuploid tumors analyzed were negative and many euploid tumors were positive (8) . The likelihood of a hybrid virus, resulting from recombination between endogenous and exogenous viruses has been proposed (2) , but analysis of the sequences described here does not support this postulate. The sequences represent a complete competent virus, closely related to MMTV.
To ascertain if the sequences reported here play a role in breast cancer pathogenesis, it is necessary to localize the sites of insertion and to show evidence for viral expression and infectivity. MMTV promotes cell growth through insertional mutagenesis, with activation or inactivation of nearby genes that are related to growth control. Thus, it is important to establish where these sequences are localized in the human genome and whether they promote expression of nearby genes. Among the multiple random insertion sites, only one may be of importance.
With regard to viral expression, it has been shown by immunofluorescence that envelope glycoprotein (gp52) expression occurred in 39% of the breast cancers studied (18) . Viral particles have been reported in 37% of breast cancer biopsies (19) , in milk (20) , and in breast cancer cell lines in culture (15) . Antibodies against gp52 have been detected in the sera of 25% of American women with breast cancer (21) , indicating immunoreactivity. By analogy to other virus-induced tumors, we can speculate that viral infection-promoting cell growth could have taken place early, but by the time breast cancer develops, only certain viral genes necessary to maintain the malignant state are expressed. We have observed viral particles in env-gene-positive specimens and are seeking specific gene activation patterns in tumors.
The presence of an env gene sequence highly homologous to MMTV in 38% of American women’s breast cancers (5) , the expression of these sequences in breast cancers (7) , the results from FISH analysis indicating presence of the env-LTR sequence only in breast cancer cells, and the identification of an entire proviral sequence in two breast carcinomas taken together support the interpretation that a substantial proportion of breast cancer is associated with retroviral sequences that may represent an HMTV.
Recently, provocative epidemiological inference for the participation of MMTV in human breast cancer has been published (22) .
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FOOTNOTES |
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1 Supported in part by the T. J. Martell
Foundation for Leukemia, Cancer, and AIDS Research; The Kash Family
Foundation; The Chemotherapy Foundation; The Jane Grinberg Research
Fund; The Ellen Block Memorial Fund; and The Myra Shaw Anti-Cancer
League. 
2 To whom requests for reprints should be
addressed, at Department of Medicine, Mount Sinai School of Medicine,
Box 1131, One Gustave L. Levy Place, New York, NY 10029. Phone:
(212) 241-8822; Fax: (212) 828-4194; E-mail: pogob01{at}doc.mssm.edu
3 The abbreviations used are: MMTV, mouse mammary
tumor virus; HERV-K10, human endogenous retrovirus K10; LTR, long
terminal repeat; MSSM, Mount Sinai School of Medicine; FISH,
fluorescence in situ hybridization; XL, extra long; ORF,
open reading frame; HMTV, human mammary tumor virus.
4 Y. Wang, I. Pelisson, S. M. Melana, J. F. Holland, and B. G-T. Pogo. Detection of MMTV-like, LTR, and
LTR-env gene sequences in human breast cancer, submitted
for publication.
5 Y. Wang, I. Pelisson, S. M. Melana, J. F.
Holland, and B. G-T. Pogo, unpublished observations.
Received 3/28/00. Accepted 12/12/00.
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