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Original Paper

Free Access

No Evidence of Mammary Tumor Virus env Gene-Like Sequences among Iranian Women with Breast Cancer

Ahangar Oskouee M.a · Shahmahmoodi S.a, e · Jalilvand S.a · Mahmoodi M.b · Ziaee A.-A.c · Esmaeili H.A.d · Mokhtari-Azad T.a · Yousefi M.a · Mollaei-Kandelous Y.a · Nategh R.a

Author affiliations

Departments of aVirology and bStatistics, School of Public Health, Tehran University of Medical Sciences, and cInstitute of Biochemistry and Biophysics, Tehran University, Tehran, dDepartment of Pathobiology, Tabriz University of Medical Sciences, Tabriz, and eFood Microbiology Research Center, Tehran University of Medical Sciences, Tehran, Iran

Corresponding Author

Shohreh Shahmahmoodi

Department of Virology, School of Public Health Tehran University of Medical Sciences

Tehran (Iran)

E-Mail shahmahmoodi@tums.ac.ir

Related Articles for ""

Intervirology 2014;57:353-356

Abstract

Objective: The mouse mammary tumor virus (MMTV) is the well-established etiological agent of mammary tumors in mice. A series of studies have implicated that a human murine mammary tumor virus-like virus occurs in human breast cancer, but it is unclear whether it has any causal role. Methods: The aim of the present study was to investigate the presence of MMTV env gene-like sequences in a group of Iranian women with or without breast cancer. A total of 65 breast cancer and 65 noncancerous breast specimens from the Department of Pathology of Tabriz University in East Azerbaijan, Iran, were analyzed by nested PCR. Results: All breast cancer and benign breast samples were negative for MMTV env gene-like DNA. Conclusion: These results indicate that the MMTV env gene-like virus may not play a significant role in the etiology of breast cancer among Iranian women.

© 2014 S. Karger AG, Basel


Introduction

Breast cancer is the most frequent cancer in women worldwide. Epidemiological studies have suggested a number of risk factors, including family history, genetic background, environmental factors, high-fat diet, nulliparity, early age of menarche, late age of menopause, and infectious agents, including viruses [1,2].

Viral etiology has been suspected but not yet proven for human breast cancer. The discovery by Bittner [3] in 1943 showed that mouse mammary tumor virus (MMTV) caused mammary cancers in mice. Consequently, MMTV has been considered as a potential etiological agent associated with breast cancer in humans. This assumption was supported by the proof that some investigators have found similar viral sequences, MMTV-like gene sequences (human murine mammary tumor virus-like virus), in human breast cancer [4,5,6,7,8]. Although there is substantial evidence that the MMTV-like virus may play a role in human breast cancer, the cause-effect theory is yet to be proven.

Breast cancer is the most frequent malignancy among Iranian women [9]. However, the epidemiological aspects of breast cancer among Iranian patients are uncertain [10]. Due to the potential importance of an association between MMTV and some cases of human breast cancer, we screened a group of Iranian women with or without breast cancer for the presence of MMTV-like sequences in breast tissues.

Materials and Methods

A total of 65 formalin-fixed paraffin-embedded breast cancer tissue blocks and 65 noncancerous breast specimens were obtained from the Pathology Department of Tabriz University in East Azerbaijan in Iran. All samples were cut and collected in sterile tubes. To avoid possible cross-contamination between specimens, special care was taken by using disposable blades and changing gloves between cutting the blocks. Deparaffinization was performed according to protocols mentioned in previous studies [11]. DNA from all samples was extracted by a QIAamp DNA FFPE tissue kit according to the manufacturer's instructions (Qiagen, Hilden, Germany). For each sample, PCR amplification with specific primers targeting a 268-bp fragment of the β-globin gene was carried out as an internal control to assess the quality of extracted DNA [12]. To identify MMTV-like sequences in breast cancer and control groups, nested PCR was carried out with primer pairs (targeting an amplicon size of 660 and 250 bp) and protocols, as mentioned in previous studies [13].

A reaction mixture containing genomic DNA, extracted from the MCF-7 human breast cancer cell line that expresses MMTV env gene-like sequences, was applied as a positive control. The amplified products were visualized on a 2% agarose gel (fig. 1).

Fig. 1

Agarose gel electrophoresis of human murine mammary tumor virus-like virus analyzed by nested PCR of breast cancer samples (1-5). Molecular weight: GeneRuler™ 100-bp DNA ladder; positive control: MCF-7 cell line.

http://www.karger.com/WebMaterial/ShowPic/151883

Results

The characteristics of the study subjects including age and histopathological types in the case and control groups are shown in table 1. In the case and control groups, respectively, 63.1 and 74.6% of specimens were less than 50 years old. The most frequent histological type of breast cancer (55.4%) was invasive ductal carcinoma II. In the control group, the most prevalent lesion was fibrocystic (81.5%).

Table 1

General characteristics of the study population

http://www.karger.com/WebMaterial/ShowPic/151884

Tissue sections obtained from 65 breast cancer paraffin-embedded blocks and 65 noncancerous breast specimens were available for analysis of MMTV-like sequences by nested PCR. DNA extracted from tissue samples was positive for the β-globin gene in all specimens, indicating that the quality and quantity of DNA were satisfactory.

In this study, all breast cancer and benign breast samples, as well as the negative controls, were all negative for MMTV env gene-like DNA.

Discussion

Breast cancer affects Iranian women at least one decade younger than their counterparts in developed countries [9]. There are many published studies about breast cancer in Iran, but the epidemiological aspects of Iranian breast cancer are uncertain.

The search for a viral cause for human breast cancer has generated considerable controversy [14,15]. MMTV has been implicated in causing mammary carcinoma in mice [3].

The contribution of MMTV in the pathogenesis of human breast cancer has long been assumed but has never been confirmed. To investigate whether MMTV-like sequences are present in breast cancer tissues in the Iranian population, 65 breast cancer and 65 benign breast samples were analyzed in this study. Our results indicate that DNA sequences that are homologous to MMTV env gene-like sequences were absent in all of the specimens.

Despite using a sensitive method, we did not detect MMTV-like sequences in human breast cancer tissue. The lack of MMTV-like sequences in our samples indicates that the concentration of these sequences is nil or very low in breast cancer tissue. Also, two other studies from Iran, in Tehran and Shiraz, have not found MMTV-like sequences in breast cancer specimens [16,17].

Although it has been reported that 32-74% of human breast cancer specimens from the USA, Italy, Australia, and Tunisia contained gene sequences homologous to the MMTV env gene [18,19,20,21], it has not been detected in breast cancer specimens from Sweden, Austria, England, Japan, Vietnam, and Mexico [14,20,22,23,24,25]. Also, a significant difference in the prevalence of antibodies reactive with MMTV and breast cancer rates has been reported between women from Western and Eastern countries. These data have revealed that the detection of the MMTV-like sequence is diverse in different geographic regions [26]. The differences in the prevalence of MMTV-like gene sequences among populations might be associated with host factors and the geographic distribution of different mouse species, as exogenous MMTV is detected in up to 50% of Mus musculus domesticus from Western countries [19,27,28].

If MMTV-like viruses were causal agents in the development of some breast cancers, it would be expected that MMTV-like sequences would be found in normal breast tissue in lower proportions than those found in breast cancer. In most studies, however, MMTV-like sequences were absent or rarely detected in normal human breast tissue from all populations. Also, Mant et al. [14] have argued that MMTV cannot play a role in human breast cancer because of the alleged histological differences between mouse mammary tumors and human breast cancers. Thus, the potential role of the MMTV-like virus in human breast cancer remains controversial.

This study does not support the involvement of MMTV-like sequences in Iranian women with breast cancer. Our findings imply that geographic and ethnic variations might play a significant role in MMTV-like virus infection and its role in breast cancer development. However, the role of MMTV-like sequences cannot be completely ruled out. To confirm the absence of MMTV-like sequences in breast cancer specimens, the results need to be verified by further studies with a larger sample size in different parts of Iran.

Acknowledgments

This study was funded and supported by the Tehran University of Medical Sciences, grant No. 91-01-27-17276. It has also been part of a PhD thesis supported by Tehran University of Medical Sciences, grant No. 240/2174.

Disclosure Statement

The authors have no conflicts of interest to declare.


References

  1. Dumitrescu R, Cotarla I: Understanding breast cancer risk - where do we stand in 2005? J Cell Mol Med 2005;9:208-221.
  2. Hedau S, Kumar U, Hussain S, Shukla S, Pande S, Jain N, Tyagi A, Deshpande T, Bhat D, Mir MM, Chakraborty S, Singh YM, Kumar R, Somasundaram K, Bharti AC, Das BC: Breast cancer and human papillomavirus infection: no evidence of HPV etiology of breast cancer in Indian women. BMC cancer 2011;11:27.
  3. Bittner JJ: Possible relationships of estrogenic hormones, genetic susceptibility, and milk influence in the production of mammary cancer in mice. Cancer Res 1942;2:710-721.
  4. Wang-Johanning FE, Nehete PN, Rycaj K, Treit J, Johanning Gl, Sastry KJ: Antigenic and immunogenic properties of envelope gene products of human endogenous retrovirus type K from breast cancer. Proc Am Assoc Cancer Res 2005;46:5127.
  5. Wang-Johanning FE, Radvanyi L, Rycaj K, Plummer JB, Yan P, Sastry KJ, Piyathilake CJ, Hunt KK, Johanning Gl: Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients. Cancer Res 2008;68:5869-5877.
  6. Wang Y, Pelisson I, Melana SM, Go V, Holland JF, Pogo BG: MMTV-like env gene sequences in human breast cancer. Arch Virol 2001;146:171-180.
  7. Lawson JS: Do viruses cause breast cancer? Methods Mol Biol 2009;471:421-438.
  8. Etkind PR, Stewart AF, Wiernik PH: Mouse mammary tumor virus (MMTV)-like DNA sequences in the breast tumors of father, mother, and daughter. Infect Agent Cancer 2008;3:2.
  9. Harirchi I, Karbakhsh M, Kashefi A, Momtahen AJ: Breast cancer in Iran: results of a multi-center study. Asian Pac J Cancer Prev 2004;5:24-27.
    External Resources
  10. Mousavi SM, Gouya MM, Ramazani R, Davanlou M, Hajsadeghi N, Seddighi Z: Cancer incidence and mortality in Iran. Ann Oncol 2008;20:55-63.
  11. Shahmahmoudi S, Mahmoodi M, Azad TM, Rad KS, Tabatabaie H, Sarijlou M, Pour YY, Yousefi M, Ghasemi M, Far KJ, Nategh R: Prevalence of mucosal types of human papillomavirus in skin lesions in north part of Iran. Cancer Lett 2007;247:72-76.
  12. Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA: Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988;239:487-497.
  13. Etkind P, Juan DU, Khan AJ, Wiernik PH: Mouse mammary tumor virus-like env gene sequences in human breast tumors and in a lymphoma of a breast cancer patient. Clin Cancer Res 2000;6:1273-1278.
    External Resources
  14. Mant C, Gillett C, D'Arrigo C, Cason J: Human murine mammary tumor virus-like agents are genetically distinct from endogenous retroviruses and are not detectable in breast cell lines or biopsies. Virology 2004;318:393-403.
  15. Lawson JS, Günzburg WH, Whitaker NJ: Viruses and human breast cancer. Future Microbiol 2006;1:33-51.
  16. Motamedifar M, Saki M, Ghaderi A: Lack of association of mouse mammary tumor virus-like sequences in Iranian breast cancer patients. Med Princ Pract 2012;21:244-248.
  17. Tabriz HM, Zendehdel K, Shahsiah R, Fereidooni F, Mehdipour B, Hosseini ZM: Lack of detection of the mouse mammary tumor-like virus (MMTV) env gene in Iranian women breast cancer using real time PCR. Asian Pac J Cancer Prev 2013;14:2945-2948.
  18. Wang Y, Holland JF, Bleiweiss IJ, Melana S, Liu X, Pelisson I, Cantarella A, Stellrecht K, Mani S, Pogo BG: Detection of mammary tumor virus env gene-like sequences in human breast cancer. Cancer Res 1995;55:5173-5179.
    External Resources
  19. Pogo BG, Melana SM, Holland JF, et al: Sequences homologous to the mouse mammary tumor virus env gene in human breast carcinoma correlate with overexpression of laminin receptor. Clin Cancer Res 1999;5:2108-2111.
    External Resources
  20. Ford CE, Tran D, Deng Y, Ta VT, Rawlinson WD, Lawson JS: Mouse mammary tumor virus-like gene sequences in breast tumors of Australian and Vietnamese women. Clin Cancer Res 2003;9:1118-1120.
  21. Hachana M, Trimeche M, Ziadi S, Amara K, Gaddas N, Mokni M, Korbi S: Prevalence and characteristics of the MMTV-like associated breast carcinomas in Tunisia. Cancer Lett 2008;27:222-230.
  22. Zapata-Benavides P, Saavedra-Alonso S, Zamora-Avila D, Vargas-Rodarte C, Barrera-Rodríguez R, Salinas-Silva J, Rodríguez-Padilla C, Tamez-Guerra R, Trejo-Avila L: Mouse mammary tumor virus-like gene sequences in breast cancer samples of Mexican women. Intervirology 2007;50:402-407.
  23. Fukuoka H, Moriuchi M, Yano H, Nagayasu T, Moriuchi H: No association of mouse mammary tumor virus-related retrovirus with Japanese cases of breast cancer. J Med Virol 2008;80:1447-1451.
  24. Bindra A, Muradrasoli S, Kisekka R, Nordgren H, Wärnberg F, Blomberg J: Search for DNA of exogenous mouse mammary tumor virus-related virus in human breast cancer samples. J Gen Virol 2007;88:1806-1809.
  25. Witt A, Hartmann B, Marton E, Zeillinger R, Schreiber M, Kubista E: The mouse mammary tumor virus-like env gene sequence is not detectable in breast cancer tissue of Austrian patients. Oncol Rep 2003;10:1025-1029.
  26. Day NK, Witkin SS, Sarkar NH, Kinne D, Jussawalla DJ, Levin A, Hsia CC, Geller N, Good RA: Antibodies reactive with murine mammary tumor virus in sera of patients with breast cancer: geographic and family studies. Proc Natl Acad Sci USA 1981;78:2483-2487.
  27. Stewart TH, Sage RD, Stewart AF, Cameron DW: Breast cancer incidence highest in the range of one species of house mouse (Mus domesticus). Br J Cancer 2000;82:446-451.
  28. Melana SM, Holland JF, Pogo BG: Search for mouse mammary tumor virus-like env sequences in cancer and normal breast from the same individuals. Clin Cancer Res 2001;7:283-294.
    External Resources

Author Contacts

Shohreh Shahmahmoodi

Department of Virology, School of Public Health Tehran University of Medical Sciences

Tehran (Iran)

E-Mail shahmahmoodi@tums.ac.ir


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: March 11, 2014
Accepted: July 30, 2014
Published online: October 15, 2014
Issue release date: December 2014

Number of Print Pages: 4
Number of Figures: 1
Number of Tables: 1

ISSN: 0300-5526 (Print)
eISSN: 1423-0100 (Online)

For additional information: https://www.karger.com/INT


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References

  1. Dumitrescu R, Cotarla I: Understanding breast cancer risk - where do we stand in 2005? J Cell Mol Med 2005;9:208-221.
  2. Hedau S, Kumar U, Hussain S, Shukla S, Pande S, Jain N, Tyagi A, Deshpande T, Bhat D, Mir MM, Chakraborty S, Singh YM, Kumar R, Somasundaram K, Bharti AC, Das BC: Breast cancer and human papillomavirus infection: no evidence of HPV etiology of breast cancer in Indian women. BMC cancer 2011;11:27.
  3. Bittner JJ: Possible relationships of estrogenic hormones, genetic susceptibility, and milk influence in the production of mammary cancer in mice. Cancer Res 1942;2:710-721.
  4. Wang-Johanning FE, Nehete PN, Rycaj K, Treit J, Johanning Gl, Sastry KJ: Antigenic and immunogenic properties of envelope gene products of human endogenous retrovirus type K from breast cancer. Proc Am Assoc Cancer Res 2005;46:5127.
  5. Wang-Johanning FE, Radvanyi L, Rycaj K, Plummer JB, Yan P, Sastry KJ, Piyathilake CJ, Hunt KK, Johanning Gl: Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients. Cancer Res 2008;68:5869-5877.
  6. Wang Y, Pelisson I, Melana SM, Go V, Holland JF, Pogo BG: MMTV-like env gene sequences in human breast cancer. Arch Virol 2001;146:171-180.
  7. Lawson JS: Do viruses cause breast cancer? Methods Mol Biol 2009;471:421-438.
  8. Etkind PR, Stewart AF, Wiernik PH: Mouse mammary tumor virus (MMTV)-like DNA sequences in the breast tumors of father, mother, and daughter. Infect Agent Cancer 2008;3:2.
  9. Harirchi I, Karbakhsh M, Kashefi A, Momtahen AJ: Breast cancer in Iran: results of a multi-center study. Asian Pac J Cancer Prev 2004;5:24-27.
    External Resources
  10. Mousavi SM, Gouya MM, Ramazani R, Davanlou M, Hajsadeghi N, Seddighi Z: Cancer incidence and mortality in Iran. Ann Oncol 2008;20:55-63.
  11. Shahmahmoudi S, Mahmoodi M, Azad TM, Rad KS, Tabatabaie H, Sarijlou M, Pour YY, Yousefi M, Ghasemi M, Far KJ, Nategh R: Prevalence of mucosal types of human papillomavirus in skin lesions in north part of Iran. Cancer Lett 2007;247:72-76.
  12. Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA: Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988;239:487-497.
  13. Etkind P, Juan DU, Khan AJ, Wiernik PH: Mouse mammary tumor virus-like env gene sequences in human breast tumors and in a lymphoma of a breast cancer patient. Clin Cancer Res 2000;6:1273-1278.
    External Resources
  14. Mant C, Gillett C, D'Arrigo C, Cason J: Human murine mammary tumor virus-like agents are genetically distinct from endogenous retroviruses and are not detectable in breast cell lines or biopsies. Virology 2004;318:393-403.
  15. Lawson JS, Günzburg WH, Whitaker NJ: Viruses and human breast cancer. Future Microbiol 2006;1:33-51.
  16. Motamedifar M, Saki M, Ghaderi A: Lack of association of mouse mammary tumor virus-like sequences in Iranian breast cancer patients. Med Princ Pract 2012;21:244-248.
  17. Tabriz HM, Zendehdel K, Shahsiah R, Fereidooni F, Mehdipour B, Hosseini ZM: Lack of detection of the mouse mammary tumor-like virus (MMTV) env gene in Iranian women breast cancer using real time PCR. Asian Pac J Cancer Prev 2013;14:2945-2948.
  18. Wang Y, Holland JF, Bleiweiss IJ, Melana S, Liu X, Pelisson I, Cantarella A, Stellrecht K, Mani S, Pogo BG: Detection of mammary tumor virus env gene-like sequences in human breast cancer. Cancer Res 1995;55:5173-5179.
    External Resources
  19. Pogo BG, Melana SM, Holland JF, et al: Sequences homologous to the mouse mammary tumor virus env gene in human breast carcinoma correlate with overexpression of laminin receptor. Clin Cancer Res 1999;5:2108-2111.
    External Resources
  20. Ford CE, Tran D, Deng Y, Ta VT, Rawlinson WD, Lawson JS: Mouse mammary tumor virus-like gene sequences in breast tumors of Australian and Vietnamese women. Clin Cancer Res 2003;9:1118-1120.
  21. Hachana M, Trimeche M, Ziadi S, Amara K, Gaddas N, Mokni M, Korbi S: Prevalence and characteristics of the MMTV-like associated breast carcinomas in Tunisia. Cancer Lett 2008;27:222-230.
  22. Zapata-Benavides P, Saavedra-Alonso S, Zamora-Avila D, Vargas-Rodarte C, Barrera-Rodríguez R, Salinas-Silva J, Rodríguez-Padilla C, Tamez-Guerra R, Trejo-Avila L: Mouse mammary tumor virus-like gene sequences in breast cancer samples of Mexican women. Intervirology 2007;50:402-407.
  23. Fukuoka H, Moriuchi M, Yano H, Nagayasu T, Moriuchi H: No association of mouse mammary tumor virus-related retrovirus with Japanese cases of breast cancer. J Med Virol 2008;80:1447-1451.
  24. Bindra A, Muradrasoli S, Kisekka R, Nordgren H, Wärnberg F, Blomberg J: Search for DNA of exogenous mouse mammary tumor virus-related virus in human breast cancer samples. J Gen Virol 2007;88:1806-1809.
  25. Witt A, Hartmann B, Marton E, Zeillinger R, Schreiber M, Kubista E: The mouse mammary tumor virus-like env gene sequence is not detectable in breast cancer tissue of Austrian patients. Oncol Rep 2003;10:1025-1029.
  26. Day NK, Witkin SS, Sarkar NH, Kinne D, Jussawalla DJ, Levin A, Hsia CC, Geller N, Good RA: Antibodies reactive with murine mammary tumor virus in sera of patients with breast cancer: geographic and family studies. Proc Natl Acad Sci USA 1981;78:2483-2487.
  27. Stewart TH, Sage RD, Stewart AF, Cameron DW: Breast cancer incidence highest in the range of one species of house mouse (Mus domesticus). Br J Cancer 2000;82:446-451.
  28. Melana SM, Holland JF, Pogo BG: Search for mouse mammary tumor virus-like env sequences in cancer and normal breast from the same individuals. Clin Cancer Res 2001;7:283-294.
    External Resources
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