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Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus

THM Stewart 1, RD Sage2, AFR Stewart 3 and DW Cameron 1

1University of Ottawa at Ottawa Hospital, General Site, Ottawa, Ontario, K1H 8M5, Canada; 2Department of Biological Sciences, University of California, Santa Barbara, CA 93106, USA; 3Department of Medicine and Graduate Program in Biochemistry and Molecular Genetics, University of Pittsburgh, PA 15213, USA

Summary Incidence of human breast cancer (HBC) varies geographically, but to date no environmental factor has explained this variation. Previously, we reported a 44% reduction in the incidence of breast cancer in women fully immunosuppressed following organ transplantation (Stewart et al (1995) Lancet 346: 796–798). In mice infected with the mouse mammary tumour virus (MMTV), immunosuppression also reduces the incidence of mammary tumours. DNA with 95% identity to MMTV is detected in 40% of human breast tumours (Wang et al (1995) Cancer Res 55: 5173–5179). These findings led us to ask whether the incidence of HBC could be correlated with the natural ranges of different species of wild mice. We found that the highest incidence of HBC worldwide occurs in lands where Mus domesticus is the resident native or introduced species of house mouse. Given the similar responses of humans and mice to immunosuppression, the near identity between human and mouse MTV DNA sequences, and the close association between HBC incidence and mouse ranges, we propose that humans acquire MMTV from mice. This zoonotic theory for a mouse-viral cause of HBC allows testable predictions and has potential importance in prevention. © 2000 Cancer Research Campaign

Keywords: human breast cancer; mouse mammary tumour virus; zoonosis; geographic variation; incidence; Mus domesticus; MMTV

Human breast cancer (HBC) incidence varies worldwide (Pa et al, 1997). People moving from areas of lower to higher H incidence show a gradually acquired increase in risk. For exa the Japanese moving to the USA (Ziegler et al, 1993), Soviet to Israel (Iscovich and Howe, 1998) and south Asians to the (Winter et al, 1999) all experience increased incidences of b cancer over a period of decades. Changes in the environme universally agreed to account for the increased risk for b cancer (Hunter et al, 1997). Genetic factors (inherited mutatio BRCA1 and BRCA2) account for about 5% of HBC (Szabo King, 1997). Diets high in fat and xeno-oestrogens have proposed to increase HBC incidence, whereas phyto-oestr may have a protective effect, although none of these hypot have shown a correlation to the migration effect (Hunter e 1996, 1997; Holmes et al, 1999). Moreover, the circumpolar have a low breast cancer incidence, half that in Canada (Mille Gaudette, 1996), but have a high saturated fat diet that is lo phyto-oestrogens and is contaminated with high levels of x oestrogens (Ayotte et al, 1997). Some other, unrecogn environmental factors with oncogenic potential must explain geographic differences in HBC incidence.

Mouse mammary tumour virus (MMTV) is an oncogenic type retrovirus that causes breast cancer in mice. MMTV gene-like sequences are found in 38–40% of HBC and are 95 identical to MMTV over 660 bp of sequence, but not to o known human endogenous retroviruses (Wang et al, 1995). T authors have recently extended these findings by isolating 9

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Received 3 March 1999 Revised 13 July 1999 Accepted 3 August 1999

Correspondence to: THM Stewart, 1 Mount Pleasant Ave, Ottawa, Ontario, Canada K1S 0L6. E-mail: [email protected]

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fragments from two human breast carcinomas containing env, gag, pol and LTR genes 94% homologous to MMTV, but only 9 homologous to each other (Liu et al, 1999). The presenc MMTV in HBC has been confirmed in two independent stu (Imai, 1996; Lushnikova et al, 1998). Similarity of the comp genomes among different MMTV strains in mice is also a 95% (Nishio et al, 1994), arguing that human MTVs are acqu from mice. These DNA findings lend credence to earlier repor MMTV-like particles (Dmochowski et al, 1969) and antibo responses to MMTV proteins (Day et al, 1981) in breast tumo

Strong support for humans becoming infected with MM comes from a study of laboratory personnel working with MM infected mice. They were found to develop a specific sero response to MMTV when compared to age- and gender-ma controls, most strongly to gp55, a surface glycoprotein of MM (Dion et al, 1986). This retrospective study was prompted reports of immune reactivity to MMTV in exposed laborat personnel (Holder et al, 1976; Wiseman et al, 1980; Lopez 1981). Most notably was the case of a woman working MMTV-infected mice. Over a 28-month period she was seron tive by enzyme-linked immunosorbent assay (ELISA) and ind immunofluorescence, but at the 32nd month she seroconv Nine months later a small mass in her right breast was discov diagnosed 3 months later as an infiltrating ductal carcinoma ( et al, 1983). From these reports and their own study, Dion (1986) recommended more stringent guidelines for labora containment of MMTV, to prevent zoonotic transmission of virus. The question remains how the general population acq the MMTV detected in breast cancer specimens.

House mice, of the genus Mus, range naturally across Asi Europe and North Africa, but do not inhabit the circump region above the treeline (Forsyth, 1985). The evolutionary tionships and biogeography of these mice are now well under

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MMTV zoonosis and human breast cancer 447

Table 1 Number of feral mouse colonies for M. musculus, M. castaneus and M. domesticus from different localities sorted by number of endogenous MMTV copies and compared to inbred M. domesticus strains

M. musculus M. castaneus M. domesticus M. domesticus (inbred)

n 12 3 13 13

MMTV copy no. 0 7 1 2 0

1–2 5 1 4 0 3–8 0 1 7 13

Each feral mouse colony was established from at least one pair of breeding founders caught at a given locality (Cohen and Varmus, 1979; Callahan et al, 1982, 1986; Jouvin-Marche et al, 1992; Imai et al, 1994). Data for inbred strains are from Kozak et al (1987). The modal number of endogenous MMTV loci in feral M. musculus is 0, for M. castaneus is 1–2, and for M. domesticus is 3–8. Feral M. domesticus mice are significantly more likely to have 3–8 endogenous loci than the other feral mice (P = 0.011 by Fisher’s exact test).

(Boursot et al, 1993; Sage et al, 1993). The taxonomy for na the evolutionary lineages of mice is contentious, some ca them three subspecies of M. musculus(Boursot et al, 1993), whil others treat them as three separate species, namely M. domesticus M. musculusand M. castaneus(Sage et al, 1993). We use the fu species taxonomy because it emphasizes the distinctiven these different mice. The native ranges of the three specie non-overlapping, and where they meet there are compara narrow zones of hybridization (Sage et al, 1993). Bro speaking, M. musculusranges from central Europe east to Ch and Japan, M. castaneusoccurs from southern China to cent Iran, and M. domesticuslives from western Iran to western Euro M. domesticusmice also expanded their range to North and S America, Australia, New Zealand and Hawaii via ships sa from western European ports. Inbred laboratory mice have m M. domesticusgenes (Callahan, 1996), although some in breeding with M. musculusimported from China and Japan h occurred (Blank et al, 1986).

MMTV has been studied mostly in inbred strains of m (Traina-Dorge and Cohen, 1983). What little is known ab MMTV in wild mice suggests that it is common and exists in e greater diversity than in inbred mice (Callahan et al, 1986). virus occurs either as independent exogenous infectious pa that cause mammary tumours or as a part of the rodent’s ge genome (endogenous provirus). Exogenous virus was detec about 50% of M. domesticusmice from Southern Californi (Rongey et al, 1973) and in 43% of M. musculusfrom Moscow (Pogossiantz, 1956). Data on the presence of exogenous v M. castaneusmice are lacking.

Mouse species differ in the numbers of endogenous MM proviral loci, with M. musculusand M. castaneushaving the fewest and M. domesticushaving the most (P < 0.02, Table 1) Laboratory colonies of feral mice have been established different geographic locations. Descendants of these wildM. musculusmice collected at six Asian (Callahan et al, 1982; Im al, 1994) and one Czech locality had no (0) complete l (Callahan et al, 1982; Jouvin-Marche et al, 1992). At two A localities (Imai et al, 1994) and two Czech localities mice had loci, and at one Austrian locality mice had 2 loci (Jouvin-Mar et al, 1992). M. castaneusmice from three Asian localities had locus (Taiwan), 1–2 loci (Indonesia) and 3 loci (Malaysia) res tively (Imai et al, 1994). Most wild M. domesticusmice assaye have been from North America, where this species was introd from Europe. Colonies were established from feral mice from Delaware–Maryland localities (Callahan et al, 1986), California localities (Cohen and Varmus, 1979), and two loca in Morocco (Callahan et al, 1982). One North American and Moroccan colony had no complete endogenous locus, 1–2 were found in one Moroccan and three North American colo and seven North American colonies had 3–5 loci. The numb endogenous loci ranges from 3 to 8 in the classical inbred s (Kozak et al, 1987). Wild M. domesticusmice from Europe hav apparently never been genotyped. However, the high numb loci in their North American descendants and in the classica strains suggests that European M. domesticuswill also have highe average numbers of proviral loci than M. musculusmice. Since the exogenous infectious particles appear to evolve repeatedly different endogenous viruses (Doolittle et al, 1989; Bra Carlson et al, 1993), and because exogenous virus can reco with endogenous virus to generate a novel variant with broad

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host range (Golovkina et al, 1994), we expect that mouse po tions with more endogenous loci will have more kinds of in tious MMTV.

Since mouse species differ in their numbers of proviral loci perhaps in the frequency of exogenous infections, we a whether HBC incidence differs in the lands of the three speci mice.

MATERIALS AND METHODS

The distribution in the number of endogenous MMTV loci in fe mouse colonies was compared for all known published report ranked in two categories: 0 complete locus and 1–2 loci in category, and 3–8 loci in the other. The proportion of observa in the different categories was compared to the distribu expected from random occurrence using Fisher’s exact tes was considered significant at the P < 0.05 level.

HBC incidence per 100 000 (world age-standardized incid rate by site), taken from Parkin et al (1997) was compared bet different countries grouped according to the natural range of resident species of house mouse (Boursot et al, 1993; Sage 1993). Two geographic regions were considered: western eastern Europe, where a clear dichotomy in the native ranges different species of house mice exists, and the rest of the w where M. domesticushas been introduced in many countries colonization from European sailing ships. Means of HBC i dence were compared by independent samples T test usin statistical program SPSS and considered significant at the P < 0.05 level.

RESULTS

In Europe there is an abrupt change in the distribution oM. domesticusand M. musculus, with a well characterized narro hybrid zone that runs through central Europe (Sage et al, 1 Figure 1A shows the western European distribution of M. domes- ticus, the eastern European distribution of M. musculusand the narrow hybrid zone (Sage et al, 1993). Figures 1B and 1C the HBC incidence (Parkin et al, 1997) in lands of M. domesticus and M. musculus. HBC incidence is 54% higher in weste

British Journal of Cancer (2000) 82(2), 446–451

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British Journal of Cancer (2000) 82(2), 446–451

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N. Ireland Belgium

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France Italy

England Switzerland

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Portugal

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Poland,Romania Slovenia,Ukraine Estonia Latvia

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M domesticus lands M musculus lands

European lands of M. domesticusthan eastern European lands M. musculus. This difference is statistically highly significa (P < 0.001, see Table 2). HBC incidence data published in for these same countries (Doll, 1969) show that the same re difference has been maintained over 30 years (data not show

Cancer incidence in Finland is higher than expected for aM. musculusland (Table 2). M. musculusmice in Finland were show to have nuclear DNA of M. musculusbut mitochondrial DNA o M. domesticus(Prager et al, 1993), suggesting that MMTV ofM. domesticusmice might also be in Finland, explaining the h incidence in Finland.

In Table 3, HBC incidence (Parkin et al, 1997) in other la having M. domesticusis compared to regions where M. domesticus is not found. Here too the incidence rates stay high (P < 0.001), even though the environments of these foreign lands vary mously in temperature, rainfall, and native biota. The pote oncogenic factor for high HBC incidence common to most o world is the presence of M. domesticusand its MMTV. We would emphasize that these strong correlations do not demonstrate but demand an explanation.

DISCUSSION

A frequently cited explanation for a high incidence of HBC standard of living. However, the relatively high standard of liv in Taiwan, Japan, Hong Kong and Singapore does not equat a high incidence of HBC, quite the contrary. The age standar rate (ASR) for Taiwan is 17 (Chie et al, 1995), Japan, 26; H Kong, 34; and Singapore, 39 (Parkin et al, 1997). In contras show that a high incidence of HBC is found in the range of mouse species.

Many parallels in mouse and HBC oncogenesis and path exist. First, in the mouse, MMTV itself does not carry a tra forming oncogene but acts as an insertional mutagen with se proviral insertion loci (Nusse, 1991). Wnt1 and Wnt3 are two genes that cause mammary tumours in mice, when activat MMTV. In women, the related genes Wnt2, Wnt4 and Wnt7bare associated with abnormal proliferation in human breast t (Huguet et al, 1994). The human homologue of mouse Wnt10b, shown to cooperate with FGF3 in the development of MM induced mouse mammary carcinomas, is upregulated in h breast carcinomas (Bui et al, 1997). These observation compatible with the effect of an insertional mutagen in wom Second, breast cancer oncogenesis in the mouse is stimula T-cell immune reaction to the superantigen of MMTV (Wei e 1993). A direct effect of MMTV superantigen is a profound unambiguous specific T-cell deletion, based predominantly oβ expression. Human T-cells also respond to MMTV-encoded s antigen with Vβ restriction (Labrecque et al, 1993). Thi immunosuppression decreases the incidence of murine cancers (Stewart and Heppner, 1997). Similarly, fully immu suppressed women (those receiving cyclosporin, azathioprin

Figure 1(A) Western European distribution of M. domesticus (heavy stippling), the eastern European distribution of M. musculus (light stippling) and the narrow hybrid zone (hatched) where both species are found (Sage et al, 1993). The boundary of M. domesticus and M. musculus distribution is poorly known in central Scandinavia (?). (B, C) HBC incidence per 100 000 annotated for each country. Incidence for N. Ireland, Belgium, Portugal, Moldova, Romania, Ukraine and Lithuania are from Doll (1969). All other values are from Parkin et al (1997)

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MMTV zoonosis and human breast cancer 449

Table 2 HBC incidence (Parkin et al, 1997) per 100 000 (world age-standardized incidence rate by site) in western European lands of M. domesticus, lands intersected by the hybrid zone, and eastern European lands of M. musculus

Lands of M. domesticus Lands of the hybrid zone Lands of M. musculus

Spain (9) 46a Croatia 37 Belarus 30 W. Germany (Saarland) 62 Yugoslavia 43 Latvia 34 Ireland 64 Slovenia 46 Estonia 36 England & Wales 69 E. Germany 48 Slovak Republic 39 Switzerland (8) 69a Norway 54 Poland (3) 40a

Italy 72 Austria (Tyrol) 65 Czech Republic 45 France (8) 75a Sweden 73 Finland 65 Iceland 79 Denmark 73 Netherlands 80

64.5 ± 13.61 53.6 ± 13.52 41.8 ± 10.06 Mean ± s.d.

Table 3 HBC incidence (Parkin et al, 1997) per 100 000 (world age-standardized incidence rate by site) in lands where M. domesticus is the resident native or introduced species of house mouse compared to lands inhabited by M. musculus, M. castaneus and other mice

Lands of M. domesticus Lands inhabited by other mice

Algeria 10 South Korea 7 Ecuador 27 Thailand (2) 12a

Costa Rica 29 Taiwan 17b

Peru (2) 31a Vietnam 18 Columbia 39 India (5) 21a

Brazil (3) 44a China (2) 26a

Puerto Rico 46 Japan (6) 26a

Argentina 60 Circumpolar Inuit 34c

Australia 67 Canada 77 New Zealand 77 Israel 77 USA (11) 79a

Uruguay (Montevideo) 93 Hawaii 97

66.0 ± 27.14 21.7 ± 8.12 Mean ± s.d.

aValues are weight means of incidence at multiple localities within a given country (number of localities indicated in parentheses). Difference between breast cancer incidence in lands of M. domesticus and other mice, P < 0.001, by independent-samples t-test. bData are from Chie et al (1995). cData are from Miller and Gaudette (1996). There are no mice of the genus Mus in the circumpolar Inuit environment (Forsyth, 1985).

steroids) show a 44% reduction in the incidence of breast ca but a significant increase in many other cancers (Stewart e 1995), supporting a parallel immune promotion of breast ca oncogenesis in humans and mice. These observations suppo hypothesis, given the finding of MMTV DNA in 38–40% of HB (Wang et al, 1995).

The possibility of a rodent-borne virus causing this ma human disease and accounting for almost half of its incid should not be surprising nor unexpected. Almost 20 years Day et al (1981) drew this same conclusion from the geogra variation in immunological responses to antigens of MMTV in sera of patients with breast cancer. Precedence for the hypo that retroviruses cause human cancers exists. For example, h T-cell leukaemia virus (HTLV-1) is associated with adult T-c leukaemia (Tajima and Cartier, 1995). There is evidence HTLV-1 was acquired by zoonotic infection from rats and m (Fukui et al, 1983). M. domesticushas lived with humans, as a

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intimate commensal, since the beginnings of agricultural soci in the Near East (Auffray et al, 1988). The existence of regula food standards allowing up to two pellets of rodent excreta pe of wheat (US pt = 551 cm3) confirm the presence of mice in th modern human food chain (Gecan et al, 1980).

A number of ‘new’ human diseases associated with rod have recently been described (Mills and Childs, 1998). M major human diseases have shifted to us from our domesti animals. Antibodies to intracytoplasmic A-type particles MMTV have been found in domesticated mammals (Zotter, 19 suggesting cross-species infectivity of MMTV. MMTV has be shown to replicate in cultured cells of rat, cat, dog, mink human breast cancer (Lasfargues et al, 1976a, 1976b, 1979; Ringold et al, 1977; Howard and Schlom, 1980). Breast infants of mothers who subsequently develop breast cance not at higher risk of developing the disease (Titus-Ernstoff e 1998), suggesting that an oncogenic human virus is not vert

British Journal of Cancer (2000) 82(2), 446–451

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transmitted from mother to infant. However, these results do exclude a zoonotic hypothesis of MMTV acquired with every n generation. Molecular and geographic evidence is becomin acceptable alternative to Koch’s postulates for identify pathogens of new diseases (Mills and Childs, 1998). The co-o rence of the highest incidence of HBC in the presence oM. domesticusleads to testable predictions.

Prediction 1

The proportion of tumours testing positive for MMTV DN should be lowest in M. musculusand M. castaneuslands. Tentative support of this prediction already exists: DNA studies of hi logical sections (Haga et al, 1994) and immunological stu (Day et al, 1981) found signs of MMTV in only 5% of patients Asian countries. The report (Wang et al, 1995) of 38–40% tumours positive for MMTV were from North American patien living in the land of M. domesticus. Moreover, the immunosup pressed transplant patients showing a 44% reduction in b cancer incidence are from western Europe and North Am (Stewart et al, 1995). A similar high incidence of MMTV DNA expected in tumours from patients living in western Europe, S America, Australia, New Zealand and Hawaii.

Prediction 2

People who live and work where M. domesticusis especially common should have a higher MMTV seroprevalence than t not so directly exposed to mice. A cross-sectional and longitu sero-epidemiological study of women attending mammogra screening clinics should be conducted. We predict that MM seronegative women will have a lower prevalence and inciden HBC compared with MMTV seropositive women.

Prediction 3

Tissues from human tumours testing positive for MMTV sho produce mammary tumours when injected into uninfected m while MMTV-negative human tumours should not. Significan the feasibility of this approach has already been demonstrat the experiments of Medvedev in the early 1950s, who was ab cause uninfected mice to develop mammary tumours w injected with extracts from human breast tumours, as cite (Pogossiantz, 1956).

If the higher incidence of HBC in lands of M. domesticus reflects oncogenic MMTV zoonosis, then this raises the real p bility of reducing breast cancer incidence by the developme an MMTV vaccine.

ACKNOWLEDGEMENTS

We thank A Badley, R Callahan, JW Carnwath, D Hölzel, J M N Sarkar and C Vutuc for helpful discussion and ideas, and following for their invaluable help: N Birkett, D Cameron, D Enria, F Furmankiewicz, G Laidlaw, C Pasqualini, J Renaud-Sk V Schusterman, N Stewart, B Theriault, N Webb and L Woodc DW Cameron was supported by a Career Scientist Award o Ontario Ministry of Health. Travel support was provided International BioImmune Systems, Inc., Great Neck, New York

British Journal of Cancer (2000) 82(2), 446–451

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REFERENCES

Auffray J-C, Tchernov E and Nevo E (1988) Origine du commensalisme de la s domestique (Mus musculus domesticus) vis-à-vis de l’homme. Comptes Rendu Acad Sci307: 517–522

Ayotte P, Dewailly E, Ryan JJ, Bruneau S and Lebel G (1997) PCBs and dioxin compounds in plasma of adult Inuit living in Nunavik (Arctic Quebec). Chemosphere34: 1459–1468

Blank RD, Campbell GR and D’Eustachio P (1986) Possible derivation of the laboratory mouse genome from multiple wild Musspecies. Genetics114: 1257–1269

Boursot P, Auffray JC, Britton-Davidian J and Bonhomme F (1993) The evoluti house mice. Annu Rev Ecol Syst24: 119–152

Brandt-Carlson C, Butel JS and Wheeler D (1993) Phylogenetic and structural analyses of MMTV LTR ORF sequences of exogenous and endogenous origins. Virology 193: 171–185

Bui TD, Rankin J, Smith K, Huguet EL, Ruben S, Strachan T, Harris AL and Lindsay S (1997) A novel human Wnt gene, WNT10B, maps to 12q13 and expressed in human breast carcinomas. Oncogene14: 1249–1253

Callahan R (1996) MMTV-induced mutations in mouse mammary tumors: their potential relevance to human breast cancer. Breast Cancer Res Treat39: 33–44

Callahan R, Drohan W, Gallahan D, D’Hoostelaere L and Potter M (1982) Nove class of mouse mammary tumor virus-related DNA sequences found in al species of Mus, including mice lacking the virus proviral genome. Proc Natl Acad Sci USA79: 4113–4117

Callahan R, Gallahan D, D’Hoostelaere LA and Potter M (1986) Endogenous MMTV proviral genomes in feral Mus musculus domesticus. Curr Top Microbiol Immunol127: 362–370

Chie WC, Chen CF, Chen CJ, Chang CL, Liaw YP and Lin RS (1995) Geograp variation of breast cancer in Taiwan: international and migrant comparison Anticancer Res15: 2745–2749

Cohen JC and Varmus HE (1979) Endogenous mammary tumour virus DNA va among wild mice and segregates during inbreeding. Nature278: 418–423

Day NK, Witkin SS, Sarkar NH, Kinne D, Jussawalla DJ, Levin A, Hsia CC, Ge N and Good RA (1981) Antibodies reactive with murine mammary tumor v in sera of patients with breast cancer: geographic and family studies. Proc Natl Acad Sci USA78: 2483–2487

Dion AS, Girardi AJ, Williams CC and Pomenti AA (1986) Serologic responses murine mammary tumor virus (MuMTV) in MuMTV-exposed laboratory personnel. J Natl Cancer Inst76: 611–619

Dmochowski L, Seman G and Gallager HS (1969) Viruses as possible etiologic factors in human breast cancer. Cancer24: 1241–1249

Doll R (1969) The geographical distribution of cancer. Br J Cancer23: 1–8 Doolittle RF, Feng DF, Johnson MS and McClure MA (1989) Origins and

evolutionary relationships of retroviruses. Q Rev Biol64: 1–30 Forsyth A (1985) Mammals of the Canadian Wild. Camden House Publishing:

London Fukui K, Noma T, Takeuchi K, Kobayashi N, Hatanaka M and Honjo T (1983)

Origin of adult T cell leukemia virus: implication for its zoonosis. Mol Biol Med1: 447–456

Gecan JS, Thrasher JL, Eisenberg W and Brickey PM (1980) Rodent excreta contamination and insect damage of wheat. J Food Protection43: 203–204

Golovkina TV, Jaffe AB and Ross SR (1994) Coexpression of exogenous and endogenous mouse mammary tumor virus RNA in vivo results in viral recombination and broadens the virus host range. J Virol 68: 5019–5026

Haga S, Imai S, Okumoto M, Mori N, Nagano K, Nishino T, Yamamoto H, Nish M, Sasaki IM, Enami J and Sarkar NH (1994) Detection of mouse mamma tumor virus related sequence in spontaneous human mammary tumor tiss Int J Oncol5: 368

Holder WD, Jr, Peer GW, Bolognesi DP and Wells SA, Jr (1976) Antibody reac with mouse mammary tumor virus in serum of breast carcinoma patients. Surg Forum27: 102–104

Holmes MD, Hunter DJ, Colditz GA, Stampfer MJ, Hankinson SE, Speizer FE, Rosner B and Willett WC (1999) Association of dietary intake of fat and fa acids with risk of breast cancer. JAMA281: 914–920

Howard DK and Schlom J (1980) Isolation of a series of novel variants of murin mammary tumor viruses with broadened host ranges. Int J Cancer25: 647–654

Huguet EL, McMahon JA, McMahon AP, Bicknell R and Harris AL (1994) Differential expression of human Wntgenes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue. Cancer Res54: 2615–2621

MMTV zoonosis and human breast cancer 451

er ast

ild

J n

isso r

tigen

ine

ous

ve st

98) 2

88.

ance

ouse

e L, nd

and C

matic

f de-

cell

R, t milk

tumor

, r

) .

GR tumor

tion

Hunter DJ, Spiegelman D, Adami HO, Beeson L, van den Brandt PA, Folsom A Fraser GE, Goldbohm RA, Graham S, Howe GR and et al. (1996) Cohort studies of fat intake and the risk of breast cancer – a pooled analysis. N Engl J Med334: 356–361

Hunter DJ, Hankinson SE, Laden F, Colditz GA, Manson JE, Willett WC, Speiz FE and Wolff MS (1997) Plasma organochlorine levels and the risk of bre cancer. N Engl J Med337: 1253–1258

Imai S (1996) Mouse mammary tumor virus and mammary tumorigenesis in w mice. Pathol Int46: 919–932

Imai S, Okumoto M, Iwai M, Haga S, Mori N, Miyashita N, Moriwaki K, Hilgers and Sarkar NH (1994) Distribution of mouse mammary tumor virus in Asia wild mice. J Virol 68: 3437–3442

Iscovich J and Howe GR (1998) Cancer incidence patterns (1972–91) among migrants from the Soviet Union to Israel. Cancer Causes Control9: 29–36

Jouvin-Marche E, Cazenave PA, Voegtle D and Marche PN (1992) V β 17 T-cell deletion by endogenous mammary tumor virus in wild-type-derived mous strain. Proc Natl Acad Sci USA89: 3232–3235

Kozak C, Peters G, Pauley R, Morris V, Michalides R, Dudley J, Green M, Dav M, Prakash O, Vaidya A and et al. (1987) A standardized nomenclature fo endogenous mouse mammary tumor viruses. J Virol 61: 1651–1654

Labrecque N, McGrath H, Subramanyam M, Huber BT and Sekaly RP (1993) Human T cells respond to mouse mammary tumor virus-encoded superan V β restriction and conserved evolutionary features. J Exp Med177: 1735–1743

Lasfargues EY, Lasfargues JC, Dion AS, Greene AE and Moore DH (1976a) Experimental infection of a cat kidney cell line with the mouse mammary tumor virus. Cancer Res36: 67–72

Lasfargues EY, Vaidya AB, Lasfargues JC and Moore DH (1976b) In vitro susceptibility of mink lung cells to the mouse mammary tumor virus. J Natl Cancer Inst57: 447–449

Lasfargues EY, Coutinho WG and Dion AS (1979) A human breast tumor cell l (BT-474) that supports mouse mammary tumor virus replication. In Vitro 15: 723–729

Liu B, Wang Y, Holland JF and Pogo BGT (1999) Sequences homologous to m mammary tumor virus in human breast cancer. Proc Am Assoc Cancer Res40: 444 (Abstract 2934)

Lopez DM, Parks WP, Silverman MA and Distasio JA (1981) Lymphoproliferati responses to mouse mammary tumor virus in lymphocyte subsets of brea cancer patients. J Natl Cancer Inst67: 353–358

Lushnikova AA, Kriukova IN, Malivanova TF, Makhov PB and Polevaia EB (19 Correlation between expression of antigen immunologically related to gp5 MMTV and transcription of homologous ENV MMTV DNA sequences in peripheral blood lymphocytes from breast cancer patients [in Russian]. Mol Gen Mikrobiol Virusol3: 33–36

Miller AB and Gaudette LA (1996) Breast cancer in Circumpolar Inuit 1969–19 Acta Oncol35: 577–580

Mills JN and Childs JE (1998) Ecologic studies of rodent reservoirs: their relev for human health. Emerg Infect Dis4: 529–537

Nishio M, Xu L, Sasaki M, Haga S, Okumoto M, Mori N, Sarkar NH, Acha-Orb H, Enami J and Imai S (1994) Complete nucleotide sequence of mouse mammary tumor virus from JYG Chinese wild mice: absence of bacterial insertion sequences in the cloned viral gaggene. Breast Cancer1: 89–94

Nusse R (1991) Insertional mutagenesis in mouse mammary tumorigenesis. Curr Top Microbiol Immunol171: 43–65

Parkin DM, Whelan SL, Raymond L and Young J (1997) Cancer Incidence in Five Continents. Vol. VII . IARC Scientific Publications: Lyon.

Pogossiantz H (1956) Some data on the experimental studies of the nature of mammary cancer in mice carried out in the Soviet Union. Acta Unio internationalis contra Cancrum12: 690–700

Poon MC, Tomana M and Niedermeier W (1983) Serum antibodies against m mammary tumor-virus-associated antigen detected nine months before appearance of a breast carcinoma. Ann Intern Med98: 937–938

Prager EM, Sage RD, Gyllensten U, Thomas WK, Hübner R, Jones CS, Nobl Searle JB and Wilson AC (1993) Mitochondrial DNA sequence diversity a the colonization of Scandinavia by house mice from East Holstein. Biol J Linn Soc50: 85–122

Ringold GM, Cardiff RD, Varmus HE and Yamamoto KR (1977) Infection of cultured rat hepatoma cells by mouse mammary tumor virus. Cell 10: 11–18

Rongey RW, Hlavackova A, Lara S, Estes J and Gardner MB (1973) Types B RNA virus in breast tissue and milk of wild mice. J Natl Cancer Inst50: 1581–1589

Sage RD, Atchley WR and Capanna E (1993) House mice as models in syste biology. Syst Biol42: 523–561

Stewart T, Tsai SC, Grayson H, Henderson R and Opelz G (1995) Incidence o novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet346: 796–798

Stewart THM and Heppner GH (1997) Immunological enhancement of breast cancer. Parasitology115: S141–153

Szabo CI and King MC (1997) Population genetics of BRCA1 and BRCA2. Am J Hum Genet60: 1013–1020

Tajima K and Cartier L (1995) Epidemiological features of HTLV-I and adult T leukemia. Intervirology38: 238–246

Titus-Ernstoff L, Egan KM, Newcomb PA, Baron JA, Stampfer M, Greenberg E Cole BF, Ding J, Willett W and Trichopoulos D (1998) Exposure to breas in infancy and adult breast cancer risk. J Natl Cancer Inst90: 921–924

Traina-Dorge V and Cohen JC (1983) Molecular genetics of mouse mammary virus. Curr Top Microbiol Immunol106: 35–56

Wang Y, Holland JF, Bleiweiss IJ, Melana S, Liu X, Pelisson I, Cantarella A Stellrecht K, Mani S and Pogo BG (1995) Detection of mammary tumo virus envgene-like sequences in human breast cancer. Cancer Res55: 5173–5179

Wei WZ, Gill RF and Wang H (1993) Mouse mammary tumor virus associated antigens and super antigens – immuno-molecular correlates of neoplasti progression. Semin Cancer Biol4: 205–213

Winter H, Cheng KK, Cummins C, Maric R, Silcocks P and Varghese C (1999 Cancer incidence in the south Asian population of England (1990–1992)Br J Cancer79: 645–654

Wiseman CL, Bowen JM, Davis JW, Hersh EM, Brown BW and Blumenschein (1980) Human lymphocyte blastogenesis responses to mouse mammary virus. J Natl Cancer Inst64: 425–430

Ziegler RG, Hoover RN, Pike MC, Hildesheim A, Nomura AM, West DW, Wu- Williams AH, Kolonel LN, Horn-Ross PL, Rosenthal JF et al (1993) Migra patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst 85: 1819–1827

Zotter S (1983) Widespread occurrence in mammals of antibodies reactive to intracytoplasmic A particles of the mouse mammary tumor virus. Arch Geschwulstforsch53: 315–319

British Journal of Cancer (2000) 82(2), 446–451

Summary
Keywords
Table-1
Materials and Methods
Results

Figure-1

Discussion

Table-2
Table-3
Prediction 1
Prediction 2
Prediction 3

Acknowledgements
References