C.86-Breast Cancer And Virus: Molecular Homology Between Human Mammary Tumor Virus 3’Orf And Scorpion Toxin, A Ligand Of Voltage-Gated Sodium Na+ Channel. Omega 3, A Na+ Channel Modifier, Reduces The Risk Of Metastatic Breast Cancer.

Présentation Poster au 5° congress européen de virology (Lyon Septembre 2013) REF 017 Category: 03.Innate immunity against viruses

Breast cancer has multiple etiologies: Many virus were implicated [Epstein-Barr virus, Human oncogenic Papillomavirus, Adenovirus, Simian Virus 40 (SV40)]. Some discrepancies (Park DJ, 2011) can be relevant to this multiplicity of viruses. Other factors can be unrecognized: Genetics, radio-activity, aluminium, genetically modified organisms.

The human homologue of Mouse Mammary Tumor Virus (MMTV) (Bittner JJ, 1936), re-called

Human Mammary Tumor Virus (HMTV), was found in human Breast Cancer (BC), in variable % of cases:  74% in Tunisia, 42% in Australia, 38% in Italy, 36% in United States, 31% in Argentina, 0.8% in Vietnam (Levine PH, 2004). This geographical disparity may depend on various factors, such as the degree of mouse infection by MMTV (Stewart TH, 2000; Szabo S, 2005). The host susceptibility or resistance to MMTV is depending on the species genetic background, particularly the T Cell Receptor (TCR) Vbeta.

The MCF-7 and MDA-MB-231 breast cancer cell lines were demonstrated to be HTMV-positive (Wang Y, 1995); when injected in nude mice, they induce metastatic breast cancer (Shafie SM, 1980; Price JE, 1990). In 123 treated breast cancers, Bougnoux P (1995) found after 48 months 70% metastasis if the breast fat alpha-linolenic acid (omega-3 precursor) level was low (9% if it was high): Thus, omega-3 (18:3n-3) protects against metastasis.

As omega-3 modifies the voltage-gated Na+ channel (NaCh) (Xiao YF, 2001; Banu I, 2006), we looked for a NaCh ligand (scorpion toxin) in HMTV.

METHODS: Amino Acid (AA) sequence comparison.

RESULTS: we found a molecular homology between HMTV 3’orf and scorpion toxin chimera (Possani LD, 2000)/Euscorpius Flavicaudus (AAT76439) (58-71) implicated in development:

We demonstrated the HMTV oncogenicity by the discovery of 2 major oncogenes in the 3'ORF:

Mdm2, the p53 ligand (Tran GMK, 2004) and Notch-1 (Tran GMK, 1998). Furthermore,  MMTV is a hormonal virus, because it integrated upstream of and activated Aromatase (Int-5), the estrogen synthetase (Tekmal RR ,1997).

CONCLUSION

HTMV has 2 major oncogenes (mdm2, the p53 ligand, and Notch-1) and is a hormonal virus integrating upstream of and activating aromatase, the estrogen synthetase. HTMV 3’orf contains a scorpion toxin, explaining the metastasis protection conferred by omega-3, a NaCh blocker.The omega-3-rich soya diet in Asia, added to the low HTMV frequency in Asia (Japan, China, Vietnam), may explain the low asian breast cancer prevalence. We suggest to use omega-3 in association with  chemotherapy in metastatic breast cancer; and study other second generation NaCh ligands (Tran GMK, Allostery EMBO Conf 2013; Djamgoz MBA, 2006).

Green tea (Yang CS, 2010) associated with mushrooms were also very interesting alicaments (breast cancer risk reduction of 89%, with an odds ratio = 0,11 (Zhang M, 2009). Corossol (graviola) was re-assessed: It down-regulates EGFR expression (Dai Y, 2011).

BIBLIOGRAPHY

Banu I, Fraser SP, Djamgoz MBA. Docosahexaenoic acid (omega-3) blocks voltage-gated sodium channel activity and migration of MDA-MB-231 human breast cancer cells. Int J Biochem Cell Biol 2006, 38: 2173–82. Bittner JJ. Some possible side effects of nursing on the mammary tumor incidence in mice. Science. 1936, 84: 162. Bougnoux P, Lhuillery C. Acides gras polyinsaturés et cancérogenèse mammaire. In : Nutrition et cancer. CERIN Symposium, Paris, 1995: 119-32. Dai Y, Hogan S, Schmelz EM et al. Selective Growth Inhibition of Human Breast Cancer Cells by Graviola Fruit Extract In Vitro and In Vivo Involving Downregulation of EGFR Expression. Nutrition Cancer 2011, 63:795-801. Djamgoz MBA and Banu I. Dietary Compounds As Anti-cancer Agents: A Preliminary Evaluation of Ion Channels And Membrane Excitability As Possible Target Mechanisms. Turkish J Biochem 2006, 31: 57–68. El Ayeb M, Darbon H, Bahraoui EM et al. Differential effects of defined chemical modifications on antigenic and pharmacological activities of scorpion alpha and beta toxins. Eur J Biochem. 1986, 155: 289-94. Kharrat R, Darbon H, Rochat H et al. Structure/activity relationships of scorpion alpha-toxins. Multiple residues contribute to the interaction with receptors. Eur J Biochem. 1989, 181: 381-90. Levine PH, Pogo BG, Klouj A et al. Increasing evidence for a human breast carcinoma virus with geographic differences. Cancer. 2004, 101: 721-6.  Park DJ, Southey MC, Giles GG, Hopper JL. No evidence of MMTV-like env sequences in specimens from the Australian Breast Cancer Family Study. Breast Cancer Res Treat. 2011, 125: 229-35.  Possani LD, Merino E, Corona M et al. Peptides and genes coding for scorpion toxins that affect ion-channels. Biochimie. 2000, 82: 861-8. Review. Price JE, Polyzos A, Zhang RD et al. Tumorigenicity and Metastasis of Human Breast Carcinoma Cell Lines in Nude Mice. Cancer Res 1990, 50: 717-21. Shafie SM, Liotta LA. Formation of metastasis by human breast carcinoma cells (MCF-7) in nude mice. Cancer Lett. 1980, 11: 81-7. Stewart TH, Sage RD, Stewart AF et al. Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus. Br J Cancer. 2000, 82: 446–51. Szabo S, Haislip AM, Garry RF. Of mice, cats, and men: Is human breast cancer a zoonosis? Microsc Res Tech. 2005, 68: 197-208. Tekmal RR, Keshava N. Role of MMTV integration locus cellular genes in breast cancer. Front Biosci. 1997, 2: d519-26. Tran MKG, Kirkiacharian S, Caprani A, Maurisson G. Molecular mimicry between HIV 1 Nef and human mdm2 ( mouse double minute 2), a ligand of p53, the major suppressor protein in oncology. XV Int AIDS Conf, Bangkok (Thailand), 2004: Abstr. WePeA5599.  Tran MKG, Kirkiacharian S. MMTV (Mouse Mammary Tumor Virus) 3'ORF mimicks the EGF family: EGF, Heregulin (c-Erb2 ligand), proto-oncogene Notch. Eurocancer 1998 (Boiron M, Marty M Ed). Paris, John Libbey Eurotext. p177 (P20). books.google.fr/books?isbn=2742002170. Tran GMK, Caprani A. Voltage-gated sodium Na+ channel allostery as the basis for the scorpion venom model of AIDS: Molecular homology between between spider toxin and HIV-2, and scorpion toxin and HIV-1 envelope gp41 sequence SWSNKS. Allostery EMBO Institut Pasteur Conf 2013, Sept 14-17, Paris. (On the site of : Positifs.org). Wang Y, Holland JF, Bleiweiss IJ et al. Detection of mammary tumor virus env gene-like sequences in human breast cancer. Cancer Res. 1995, 55: 5173-9. Xiao YF, Wright SN, Wang GK et al. Fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the alpha-subunit of the human cardiac Na+ channel. Proc Natl Acad Sci U S A. 1998, 9: 2680-5.  Yang CS & Wang X . Green Tea and Cancer Prevention. Nutrition Cancer 2010, 62: 931-7. Zhang M, Huang J, Xie X, Holman CD. Dietary intakes of mushrooms and green tea combine to reduce the risk of breast cancer in Chinese women. Int J Cancer. 2009, 124: 1404-8. Acknowledgements: Association Positifs.