Download Recent developments linking retroviruses to human breast cancer

Journal of General Virology (2014), 95, 2589–2593
Review
DOI 10.1099/vir.0.070631-0
Recent developments linking retroviruses to human
breast cancer: infectious agent, enemy within or
both?
Brian Salmons,1 James S. Lawson2 and Walter H. Günzburg3
Correspondence
Brian Salmons
[email protected]
1
Austrianova, 20 Biopolis Way, 05-518 Centros, Republic of Singapore 138668
2
School of Public Health, University of New South Wales, Sydney, Australia
3
Institute of Virology, Department of Pathobiology, University of Veterinary Medicine,
Veterinaerplatz 1, 1210 Vienna, Austria
Received 30 July 2014
Accepted 10 September 2014
Evidence is accumulating that one or more beta-retrovirus is associated with human breast
cancer. Retroviruses can exist as an infectious (exogenous) virus or as a part of the genetic
information of cells due to germline integration (endogenous). An exogenous virus with a genome
that is highly homologous to mouse mammary tumour virus is gaining acceptance as possibly
being associated with human breast cancer, and recently furnished evidence is discussed in this
article, as is the evidence for involvement of an endogenous human beta-retrovirus, HERV-K.
Modes of interaction are also reviewed and linkages to the APOBEC3 family are suggested.
Background
Human breast cancer and MMTV
It has long been speculated that retroviruses might play a
role in human breast cancer. Initial interest focused on a
potential role for mouse mammary tumour virus (MMTV)
and a quite comprehensive review on the early evidence for
this appeared in Nature as early as 1971 (Moore et al.,
1971). This and later papers published described the
detection of virus particles, virus proteins and antibodies
that react with MMTV in the serum of patients, and the
presence of MMTV-related nucleic acids in breast cancers.
However, in the 1980s, MMTV-related endogenous sequences (HERVs) were discovered and they seemed to
provide an explanation for most of the evidence that
had amassed implicating MMTV in human breast cancer
(Lawson et al., 2006). Moreover, this discovery spawned a
new hypothesis that HERVs, and in particular HERV-K,
play a potential role in the development of breast cancer.
This view was challenged in the mid-1990s, when the work
of the group of Beatriz Pogo (Wang et al., 1995), quickly
followed by others, showed that MMTV or a virus like it
might be a cause of at least some cases of breast cancer in
humans (reviewed by Lawson et al., 2006). The Pogo group
alone has identified the presence of an MMTV proviral
structure in human breast cancer cells (Liu et al., 2001),
and shown the presence of virus particles produced by
primary human breast cancer cells (Melana et al., 2007)
and of virus proteins in human breast cancer cells (Melana
et al., 2010). Importantly, many of these findings have been
confirmed and extended by other groups (reviewed by
Lawson et al., 2006), albeit not by all researchers (reviewed
by Joshi & Buehring, 2012).
The heightened interest in MMTV as a human breast
cancer virus is reflected by the fact that in the last year
alone there have been a number of reviews on the key
evidence that MMTV, or a highly related virus, is present in
a proportion of human breast cancers (Mason et al., 2011;
Alibek et al., 2013; Salmons & Günzburg, 2013). Naushad
and colleagues have also recently published a primary
analysis of the prevalence of MMTV in the Pakistani
population. They amplified a 666 bp MMTV envelope and
a 630 bp LTR sequence from tissue biopsies and peripheral
blood from breast cancer patient samples and detected
MMTV-like virus env and LTR DNA sequences in 20 and
26 % of breast tumour samples, respectively, from a total of
80. In this study, no significant association was observed
between age, grade of disease or lymph node involvement
and the prevalence of MMTV-like sequences (Naushad
et al., 2014). A second recently published comprehensive
meta-analysis in which 22 previous studies were analysed
with respect to the association between MMTV infection as
detected by PCR-based techniques and breast cancer
concluded that MMTV infection significantly increases
the risk of breast cancer, by about 15-fold. However, even
though the data included in this study had to fulfil a
number of well-defined criteria, the meta-analysis was
limited by substantial heterogeneity across studies due to
differences in cell selection methods and/or detection
methods used. Nevertheless, the prevalence of MMTV in
breast cancer tissue was much higher in Western patients
than in Asians, in line with what had previously been
concluded (Wang et al., 2014).
070631 G 2014 The Authors
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 29 Apr 2017 22:28:40
Printed in Great Britain
2589
B. Salmons, J. S. Lawson and W. H. Günzburg
Excitingly, a recent publication by Pogo and colleagues has
recently provided new evidence that a virus highly related
to MMTV might be involved in human breast cancer
(Nartey et al., 2014). This paper reports the presence of the
virus [named by the authors ‘human mammary tumour
virus’ (HMTV)] in milk from lactating women. In this
study, milk from two groups of woman was compared: (1)
one who had undergone breast biopsies on suspicion of
breast cancer at some point in their lives or were scheduled
for breast biopsy on the basis of either clinical or
radiological findings (high risk of breast cancer); and (2)
one without biopsies as a control group. The major finding
of the study was that although MMTV-related sequences
could be found in both groups, the high-risk group that
had undergone or were about to undergo biopsy showed a
threefold higher positivity for the virus.
These three recent studies support the notion that an
MMTV-like virus may be involved in at least some cases
of human breast cancer and also go some way towards
answering some of the issues raised by other commentators
(Lawson et al., 2006; Mason et al., 2011; Salmons &
Günzburg, 2013).
The Pogo group study was not the first to demonstrate the
presence of MMTV in human milk (Johal et al., 2011) and
there is thus some comfort from the fact that two
independent groups have shown this. Nevertheless, there
are some issues and caveats. The percentage of patients
showing MMTV-like sequences (20.55 %) in the milk
(Nartey et al., 2014) is somewhat lower than the 38–40 %
previously reported by that and other groups (Lawson et al.,
2006). This may be due to the fact that the study group was
a high-risk group rather than to women who actually had
breast cancer, in which the incidence was 38–40 %. The
virus appears also to have been detected in a crude pellet in
this study (Nartey et al., 2014) and thus formally may not
have been virus, but rather DNA/RNA associated with
particulate matter. Ideally, virions should have been
isolated by isopycnic banding to strengthen the contention
that the PCR signal came from a virus. Admittedly, if too
little virus was present this could have been an issue;
however, it should be noted that MMTV-infected mouse
milk contains enough particles to allow this (Salmons &
Günzburg, 1987; Ross, 2010). We recently discussed the
issue that, even though MMTV sequences have been
detected in human breast cancer tissue, highly sensitive
detection methods often have to be used, implying that
relatively low levels of virus are present as compared with
those in mice (Salmons & Günzburg, 2013). This has implications for the mechanisms of tumorigenesis: although it is
quite clear that MMTV influences mouse cellular genes by
enhancer insertion and that a number of these genes
activated in the mouse are activated in human breast cancer
(Callahan et al., 2012), including wnt-1 (Lawson et al.,
2010), the likelihood of this happening in humans is linked
to the number of infection events with a randomly
integrating virus like MMTV (Faschinger et al., 2008),
which suggests that the likelihood of a relatively low-titre
2590
virus integrating near one of the genes associated with breast
cancer is quite low. Other putative mechanisms of virusmediated tumorigenesis have recently been discussed
(Salmons & Günzburg, 2013).
Another issue is that all of the studies to date have looked
at the presence of MMTV env (or LTR) sequences because
this region shows most sequence divergence from HERVs,
but this would strengthen the contention that a virus is
present if the authors had also looked for gag and/or pol
sequences, although presumably they can still do this.
Worryingly, in the study of Nartey and colleagues, mouse
DNA was found to be present in one of the DNA samples
and, while all the other samples were shown to be negative
for mouse DNA sequences (Nartey et al., 2014), this is a
potential reason for concern. Another potential inconsistency is that that study suggests a hormonal linkage between
HMTV (MMTV) infection and breast cancer (Nartey et al.,
2014), in line with their previous findings in gestational
breast cancer (Wang et al., 2003). However, the metadata
analysis reported by Wang and colleagues which includes
these data concludes a lack of positive association between
MMTV infection and expression of ER, PR, HER2, p53
or histological grades (Wang et al., 2014), so further
independent studies may be required to clarify this.
Human cancer and HERVs
As mentioned above, there appear to be two camps
advocating a role for a human retrovirus in breast cancer –
one endorsing endogenous HERVs as perpetrators and
the other exogenous MMTV. A number of groups have
provided evidence to support a role for HERV in breast
cancer (for recent reviews see Cegolon et al., 2013; Downey
et al., 2014). Although a recent study examining the prevalence of integrated forms of two common HERV-K
proviruses failed to find a significant difference between
individuals diagnosed with breast cancer and those without
history of the disease, the authors point out that their
findings do not rule out the possibility that rarer HERV-K
proviruses are involved in a subset of breast cancers or will
provide a meaningful biomarker of this disease
(Wildschutte et al., 2014). Indeed, most recently, antibodies against HERV-K and HERV-K-specific mRNA have
been proposed as serum biomarkers of early stage breast
cancer (Wang-Johanning et al., 2014).
The involvement of an MMTV-like virus or HERV-K
in human breast cancer is not necessarily an ‘either/or’
situation (i.e. they are not mutually exclusive). Even in the
mouse, it is documented that both endogenous and
exogenous viruses individually can cause mammary
tumours (Salmons & Günzburg, 1987; Ross, 2010), but
perhaps crucially they can also jointly play a role in
tumorigenesis. This cooperation can be in the form of
direct interaction, for example in GR mice. Mammary
tumours in GR mice have been linked to the endogenous
provirus Mtv-2, which produces an exogenous virus, but
also the endogenous provirus Mtv-17 produces transcripts
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 29 Apr 2017 22:28:40
Journal of General Virology 95
Beta-retroviruses and human breast cancer
that can be packaged into virions, shed into milk and
contribute to recombinant proviruses. These recombinant
proviruses essentially consist of an Mtv-2 sequence with the
envelope sequences from Mtv-17, and such recombinant
proviruses are found in a small percentage of virus-induced
mammary tumours (Golovkina et al., 1996). In this respect, it is of interest that the integration pattern of a
resurrected HERV-K, in which various fragments of defective HERV-K virus genomes were linked together to
produce an infectious provirus, was shown to resemble
that of MMTV (Faschinger et al., 2008; Brady et al., 2009).
Additionally, an indirect role of endogenous MMTV
proviruses, in which super-antigens encoded by the
endogenous proviruses contribute to tumorigenesis by
shaping the host immune system, has been documented
(reviewed by Holt et al., 2013). Although MMTV-specific
super-antigen primers are able to amplify sequences from
the human genome (Indraccolo et al., 1995), to date there
is little evidence that HERVs encode super-antigens.
As well as recombinant viruses, there is also the potential
for the production of pseudotyped viruses. Heidmann’s
group showed some years ago that the envelope of HERVK108 is functional in that it can pseudoptye simian immunodeficiency virus and confer infectivity (Dewannieux et al.,
2005). Moreover, a resurrected, consensus HERV envelope
has been shown capable of forming pseudtoypes with human
immunodeficiency virus (HIV) (Lee & Bieniasz, 2007). It
remains to be determined whether pseudotypes consisting of
virion components from HERV and MMTV can be
produced in cell culture, let alone in vivo.
Retroviruses can interact with each other and modify
disease induction. HERV-K activation and co-expression
with HIV-1 has been observed during HIV-1 infection.
Monde and colleagues found that the release efficiency of
HIV-1 Gag was reduced by threefold when the HERV-K
Gag was co-expressed and that HERV-K Gag co-localized
with HIV-1 Gag at the plasma membrane and co-assembled
in virus particles, leading to a similar reduction in HIV-1
infectivity (Monde et al., 2012). These findings raise the
possibility that both exogenous and endogenous viruses may
cooperate to cause human breast cancer and would help
explain the differences between the classical mechanisms of
tumour induction that have been described for MMTV in
the mouse. Some potential mechanisms of tumorigenesis
have been discussed previously (Salmons & Günzburg,
2013), although only in the context of an MMTV-like virus
playing a role.
A central role for APOBEC3 in breast and other
cancers
Cellular enzymes of the apolipoprotein B editing complex
(APOBEC) family encode deaminase enzymes that edit
DNA and/or RNA sequences and play a central role in the
control of virus infections, including retroviruses. APOBEC
enzymes normally function in innate immune responses,
http://vir.sgmjournals.org
including those that target retroviruses, suggesting links
between mutagenesis, immunity and viral infection in the
process of cancer development (Henderson et al., 2014). Many
viruses have evolved mechanisms to counteract APOBEC
effects, and thus drugs enhancing APOBEC activity are being
developed. Interestingly, inactivating mutations and deletions in APOBEC3 seem to play a possible role in breast
cancer development. This could lead to activation or
enhanced expression of exogenous and endogenous retroviruses, as proposed by Downey and colleagues (Downey
et al., 2014). Aberrant expression of APOBEC3 has also been
shown to be induced by DNA viruses such as human
papilloma virus, specifically in breast cancer (Ohba et al.,
2014), and also a deletion polymorphism involving the
APOBEC3 gene cluster on chromosome 22 is associated
with elevated risk of breast cancer (Long et al., 2013; NikZainal et al., 2014). Moreover, a specific APOBEC mutation
pattern has been described in a number of cancers, including
breast cancer, in particular the HER2-enriched subtype of
breast cancers, suggesting that this is functionally linked with
cancer development (Roberts et al., 2013). This mutation
pattern has been show to be linked to APOBEC3B expression
specifically in breast cancer and leads to DNA damage that
could select TP53 inactivation, thereby resulting in tumour
heterogeneity (Burns et al., 2013). Taken together, all of these
studies suggest that the APOBEC family and particularly
APOBEC3 may play a central role in the early stages of breast
cancer induction (Lawson, 2014). However, although an
intriguing possibility, additional studies are required to
formally demonstrate a link between MMTV and/or HERVK and APOBEC family members and breast cancer.
Next-generation information on retroviruses and
breast cancer
The advent of next-generation sequencing offers a much
more comprehensive means to study retroviral integration
sites and has been employed, for example, by Marchi
and colleagues to analyse potential integration sites in the
DNA of 358 individuals that may not be present in the
human reference genome sequence (Marchi et al., 2014).
Interestingly, they found 17 novel HERV-K integration loci
using this technique.
Similarly, Shingo Miyauchi, working in Sydney, Australia,
has preliminary data based on next-generation sequencing
(S. Miyauchi, unpublished), which confirm the presence of
MMTV env sequences in breast cancers. While these
findings must be verified, the data are supportive of the
PCR-based findings that MMTV env sequences are present
in breast cancers that have developed in women from many
countries (Wang et al., 2014).
Conclusion
Slowly evidence is amassing that a retrovirus might be
involved in certain cases of human breast cancer, but there
is still a long way to go. Many groups have found evidence
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 29 Apr 2017 22:28:40
2591
B. Salmons, J. S. Lawson and W. H. Günzburg
for the potential involvement in human breast cancer of a
virus highly homologous to MMTV, a well-known aetiological agent of mammary cancer in mice. Recent data have
confirmed and extended support for a role of MMTV (or
its human homologue, HMTV), but HERV-K as well as
other viruses could also play a role either individually or in
concert, perhaps via APOBEC enzymes. The lack of many
of the hallmarks of MMTV-induced tumours supports the
notion of both viruses acting in concert (assuming that a
virus is indeed involved). The next few years may finally see
general acceptance that retroviruses play a seminal role in
the development of breast cancer as well as the development
of diagnostic tools and potential antiviral therapies.
Indraccolo, S., Günzburg, W. H., Leib-Mösch, C., Erfle, V. & Salmons,
B. (1995). Identification of three human sequences with viral
superantigen-specific primers. Mamm Genome 6, 339–344.
Johal, H., Ford, C., Glenn, W., Heads, J., Lawson, J. & Rawlinson, W.
(2011). Mouse mammary tumor like virus sequences in breast milk
from healthy lactating women. Breast Cancer Res Treat 129, 149–
155.
Joshi, D. & Buehring, G. C. (2012). Are viruses associated with human
breast cancer? Scrutinizing the molecular evidence. Breast Cancer Res
Treat 135, 1–15.
Lawson, J. S. (2014). Newly identified causal mechanisms in human
papilloma virus associated breast cancer. PLoS ONE.
Lawson, J. S., Günzburg, W. H. & Whitaker, N. J. (2006). Viruses and
human breast cancer. Future Microbiol 1, 33–51.
Acknowledgements
Lawson, J. S., Glenn, W. K., Salmons, B., Ye, Y., Heng, B., Moody, P.,
Johal, H., Rawlinson, W. D., Delprado, W. & other authors (2010).
The authors thank Shingo Miyauchi, Sydney, Australia, for allowing
the inclusion of preliminary unpublished data.
Lee, Y. N. & Bieniasz, P. D. (2007). Reconstitution of an infectious
Mouse mammary tumor virus-like sequences in human breast cancer.
Cancer Res 70, 3576–3585.
human endogenous retrovirus. PLoS Pathog 3, e10.
Liu, B., Wang, Y., Melana, S. M., Pelisson, I., Najfeld, V., Holland, J. F.
& Pogo, B. G. (2001). Identification of a proviral structure in human
References
Alibek, K., Kakpenova, A., Mussabekova, A., Sypabekova, M. &
Karatayeva, N. (2013). Role of viruses in the development of breast
breast cancer. Cancer Res 61, 1754–1759.
cancer. Infect Agent Cancer 8, 32.
Long, J., Delahanty, R. J., Li, G., Gao, Y.-T., Lu, W., Cai, Q., Xiang, Y.-B.,
Li, C., Ji, B.-T. & other authors (2013). A common deletion in the
Brady, T., Lee, Y. N., Ronen, K., Malani, N., Berry, C. C., Bieniasz, P. D. &
Bushman, F. D. (2009). Integration target site selection by a resurrected
APOBEC3 genes and breast cancer risk. J Natl Cancer Inst 105, 573–
579.
human endogenous retrovirus. Genes Dev 23, 633–642.
Marchi, E., Kanapin, A., Magiorkinis, G. & Belshaw, R. (2014).
Burns, M. B., Lackey, L., Carpenter, M. A., Rathore, A., Land, A. M.,
Leonard, B., Refsland, E. W., Kotandeniya, D., Tretyakova, N. & other
authors (2013). APOBEC3B is an enzymatic source of mutation in
Unfixed endogenous retroviral insertions in the human population.
J Virol 88, 9529–9537.
breast cancer. Nature 494, 366–370.
tumor virus in human breast cancer. Red herring or smoking gun?
Am J Pathol 179, 1588–1590.
Mason, A. L., Gilady, S. Y. & Mackey, J. R. (2011). Mouse mammary
Callahan, R., Mudunur, U., Bargo, S., Raafat, A., McCurdy, D.,
Boulanger, C., Lowther, W., Stephens, R., Luke, B. T. & other authors
(2003). Genes affected by mouse mammary tumor virus (MMTV)
Melana, S. M., Nepomnaschy, I., Sakalian, M., Abbott, A., Hasa, J.,
Holland, J. F. & Pogo, B. G. (2007). Characterization of viral particles
proviral insertions in mouse mammary tumors are deregulated or
mutated in primary human mammary tumors. Oncotarget 3, 1320–1334.
isolated from primary cultures of human breast cancer cells. Cancer
Res 67, 8960–8965.
Cegolon, L., Salata, C., Weiderpass, E., Vineis, P., Palù, G. &
Mastrangelo, G. (2013). Human endogenous retroviruses and cancer
Melana, S. M., Nepomnaschy, I., Hasa, J., Djougarian, A., Djougarian,
A., Holland, J. F. & Pogo, B. G. (2010). Detection of human mammary
prevention: evidence and prospects. BMC Cancer 13, 4.
Dewannieux, M., Blaise, S. & Heidmann, T. (2005). Identification of a
tumor virus proteins in human breast cancer cells. J Virol Methods
163, 157–161.
functional envelope protein from the HERV-K family of human
endogenous retroviruses. J Virol 79, 15573–15577.
Monde, K., Contreras-Galindo, R., Kaplan, M. H., Markovitz, D. M. &
Ono, A. (2012). Human endogenous retrovirus K Gag coassembles
Downey, R. F., Sullivan, F. J., Wang-Johanning, F., Ambs, S., Giles,
F. J. & Glynn, S. A. (2014). Human endogenous retrovirus K and
with HIV-1 Gag and reduces the release efficiency and infectivity of
HIV-1. J Virol 86, 11194–11208.
cancer: innocent bystander or tumorigenic accomplice? Int J Cancer
doi:10.1002/ijc.29003 [Epub ahead of print].
Moore, D. H., Charney, J., Kramarsky, B., Lasfargues, E. Y., Sarkar, N. H.,
Brennan, M. J., Burrows, J. H., Sirsat, S. M., Paymaster, J. C. & Vaidya,
A. B. (1971). Search for a human breast cancer virus. Nature 229, 611–615.
Faschinger, A., Rouault, F., Sollner, J., Lukas, A., Salmons, B.,
Günzburg, W. H. & Indik, S. (2008). Mouse mammary tumor virus
integration site selection in human and mouse genomes. J Virol 82,
1360–1367.
Nartey, T., Moran, H., Marin, T., Arcaro, K. F., Anderton, D. L., Etkind,
P., Holland, J. F., Melana, S. M. & Pogo, B. G. (2014). Human
Golovkina, T. V., Prakash, O. & Ross, S. R. (1996). Endogenous
mammary tumor virus (HMTV) sequences in human milk. Infect
Agent Cancer 9, 20.
mouse mammary tumor virus Mtv-17 is involved in Mtv-2-induced
tumorigenesis in GR mice. Virology 218, 14–22.
Naushad, W., Bin Rahat, T., Gomez, M. K., Ashiq, M. T., Younas, M. &
Sadia, H. (2014). Detection and identification of mouse mammary
Henderson, S., Chakravarthy, A., Su, X., Boshoff, C. & Fenton, T. R.
(2014). APOBEC-mediated cytosine deamination links PIK3CA
tumor virus-like DNA sequences in blood and breast tissues of breast
cancer patients. Tumour Biol 35, 8077–8086.
helical domain mutations to human papillomavirus-driven tumor
development. Cell Rep 7, 1833–1841.
Holt, M. P., Shevach, E. M. & Punkosdy, G. A. (2013). Endogenous
Nik-Zainal, S., Wedge, D. C., Alexandrov, L. B., Petljak, M., Butler,
A. P., Bolli, N., Davies, H. R., Knappskog, S., Martin, S. & other authors
(2014). Association of a germline copy number polymorphism of
mouse mammary tumor viruses (Mtv): new roles for an old virus in
cancer, infection, and immunity. Front Oncol 3, 287.
APOBEC3A and APOBEC3B with burden of putative APOBECdependent mutations in breast cancer. Nat Genet 46, 487–491.
2592
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 29 Apr 2017 22:28:40
Journal of General Virology 95
Beta-retroviruses and human breast cancer
Ohba, K., Ichiyama, K., Yajima, M., Gemma, N., Nikaido, M., Wu, Q.,
Chong, P., Mori, S., Yamamoto, R. & other authors (2014). In vivo
of mammary tumor virus env gene-like sequences in human breast
cancer. Cancer Res 55, 5173–5179.
and in vitro studies suggest a possible involvement of HPV infection
in the early stage of breast carcinogenesis via APOBEC3B induction.
PLoS ONE 9, e97787.
Wang, Y., Melana, S. M., Baker, B., Bleiweiss, I., Fernandez-Cobo,
M., Mandeli, J. F., Holland, J. F. & Pogo, B. G. T. (2003). High
Roberts, S. A., Lawrence, M. S., Klimczak, L. J., Grimm, S. A., Fargo,
D., Stojanov, P., Kiezun, A., Kryukov, G. V., Carter, S. L. & other
authors (2013). An APOBEC cytidine deaminase mutagenesis pattern
is widespread in human cancers. Nat Genet 45, 970–976.
Ross, S. R. (2010). Mouse mammary tumor virus molecular biology
and oncogenesis. Viruses 2, 2000–2012.
Salmons, B. & Günzburg, W. H. (1987). Current perspectives in the
biology of mouse mammary tumour virus. Virus Res 8, 81–102.
prevalence of MMTV-like env gene sequences in gestational breast
cancer. Med Oncol 20, 233–236.
Wang, F., Hou, J., Shen, Q., Yue, Y., Xie, F., Wang, X. & Jin, H.
(2014). Mouse mammary tumor virus-like virus infection and the
risk of human breast cancer: a meta-analysis. Am J Transl Res 6,
248–266.
Wang-Johanning, F., Li, M., Esteva, F. J., Hess, K. R., Yin, B., Rycaj, K.,
Plummer, J. B., Garza, J. G., Ambs, S. & Johanning, G. L. (2014).
Salmons, B. & Günzburg, W. H. (2013). Revisiting a role for a
Human endogenous retrovirus type K antibodies and mRNA as serum
biomarkers of early-stage breast cancer. Int J Cancer 134, 587–595.
mammary tumor retrovirus in human breast cancer. Int J Cancer 133,
1530–1535.
Wildschutte, J. H., Ram, D., Subramanian, R., Stevens, V. L. & Coffin,
J. M. (2014). The distribution of insertionally polymorphic endogen-
Wang, Y., Holland, J. F., Bleiweiss, I. J., Melana, S., Liu, X., Pelisson, I.,
Cantarella, A., Stellrecht, K., Mani, S. & Pogo, B. G. (1995). Detection
ous retroviruses in breast cancer patients and cancer-free controls.
Retrovirology 11, 62.
http://vir.sgmjournals.org
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 29 Apr 2017 22:28:40
2593