Mouse Mammary Tumour Virus (MMTV) in Human Breast Cancer—The Value of Bradford Hill Criteria
For many decades, the betaretrovirus, mouse mammary tumour virus (MMTV), has been a causal suspect for human breast cancer. In recent years, substantial new evidence has been developed. Based on this evidence, we hypothesise that MMTV has a causal role. We have used an extended version of the classi...
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MDPI AG
2022-03-01
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| Online Access: | https://www.mdpi.com/1999-4915/14/4/721 |
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| author | James S. Lawson Wendy K. Glenn |
| author_facet | James S. Lawson Wendy K. Glenn |
| author_sort | James S. Lawson |
| collection | DOAJ |
| description | For many decades, the betaretrovirus, mouse mammary tumour virus (MMTV), has been a causal suspect for human breast cancer. In recent years, substantial new evidence has been developed. Based on this evidence, we hypothesise that MMTV has a causal role. We have used an extended version of the classic A. Bradford Hill causal criteria to assess the evidence. 1. Identification of MMTV in human breast cancers: The MMTV 9.9 kb genome in breast cancer cells has been identified. The MMTV genome in human breast cancer is up to 98% identical to MMTV in mice. 2. Epidemiology: The prevalence of MMTV positive human breast cancer is about 35 to 40% of breast cancers in Western countries and 15 to 20% in China and Japan. 3. Strength of the association between MMTV and human breast cancer: Consistency—MMTV env gene sequences are consistently five-fold higher in human breast cancer as compared to benign and normal breast controls. 4. Temporality (timing) of the association: MMTV has been identified in benign and normal breast tissues up to 10 years before the development of MMTV positive breast cancer in the same patient. 5. Exposure: Exposure of humans to MMTV leads to development of MMTV positive human breast cancer. 6. Experimental evidence: MMTVs can infect human breast cells in culture; MMTV proteins are capable of malignantly transforming normal human breast epithelial cells; MMTV is a likely cause of biliary cirrhosis, which suggests a link between MMTV and the disease in humans. 7. Coherence—analogy: The life cycle and biology of MMTV in humans is almost the same as in experimental and feral mice. 8. MMTV Transmission: MMTV has been identified in human sputum and human milk. Cereals contaminated with mouse fecal material may transmit MMTV. These are potential means of transmission. 9. Biological plausibility: Retroviruses are the established cause of human cancers. Human T cell leukaemia virus type I (HTLV-1) causes adult T cell leukaemia, and human immunodeficiency virus infection (HIV) is associated with lymphoma and Kaposi sarcoma. 10. Oncogenic mechanisms: MMTV oncogenesis in humans probably differs from mice and may involve the enzyme APOBEC3B. Conclusion: In our view, the evidence is compelling that MMTV has a probable causal role in a subset of approximately 40% of human breast cancers. |
| first_indexed | 2024-03-09T12:53:04Z |
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| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T12:53:04Z |
| publishDate | 2022-03-01 |
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| spelling | doaj.art-963f5e8b5b9f4d979463716e9b577e322023-11-30T22:03:26ZengMDPI AGViruses1999-49152022-03-0114472110.3390/v14040721Mouse Mammary Tumour Virus (MMTV) in Human Breast Cancer—The Value of Bradford Hill CriteriaJames S. Lawson0Wendy K. Glenn1School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, AustraliaSchool of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, AustraliaFor many decades, the betaretrovirus, mouse mammary tumour virus (MMTV), has been a causal suspect for human breast cancer. In recent years, substantial new evidence has been developed. Based on this evidence, we hypothesise that MMTV has a causal role. We have used an extended version of the classic A. Bradford Hill causal criteria to assess the evidence. 1. Identification of MMTV in human breast cancers: The MMTV 9.9 kb genome in breast cancer cells has been identified. The MMTV genome in human breast cancer is up to 98% identical to MMTV in mice. 2. Epidemiology: The prevalence of MMTV positive human breast cancer is about 35 to 40% of breast cancers in Western countries and 15 to 20% in China and Japan. 3. Strength of the association between MMTV and human breast cancer: Consistency—MMTV env gene sequences are consistently five-fold higher in human breast cancer as compared to benign and normal breast controls. 4. Temporality (timing) of the association: MMTV has been identified in benign and normal breast tissues up to 10 years before the development of MMTV positive breast cancer in the same patient. 5. Exposure: Exposure of humans to MMTV leads to development of MMTV positive human breast cancer. 6. Experimental evidence: MMTVs can infect human breast cells in culture; MMTV proteins are capable of malignantly transforming normal human breast epithelial cells; MMTV is a likely cause of biliary cirrhosis, which suggests a link between MMTV and the disease in humans. 7. Coherence—analogy: The life cycle and biology of MMTV in humans is almost the same as in experimental and feral mice. 8. MMTV Transmission: MMTV has been identified in human sputum and human milk. Cereals contaminated with mouse fecal material may transmit MMTV. These are potential means of transmission. 9. Biological plausibility: Retroviruses are the established cause of human cancers. Human T cell leukaemia virus type I (HTLV-1) causes adult T cell leukaemia, and human immunodeficiency virus infection (HIV) is associated with lymphoma and Kaposi sarcoma. 10. Oncogenic mechanisms: MMTV oncogenesis in humans probably differs from mice and may involve the enzyme APOBEC3B. Conclusion: In our view, the evidence is compelling that MMTV has a probable causal role in a subset of approximately 40% of human breast cancers.https://www.mdpi.com/1999-4915/14/4/721breast cancermouse mammary tumour viruscausationtransmissiononcogenic mechanismsvirus identification |
| spellingShingle | James S. Lawson Wendy K. Glenn Mouse Mammary Tumour Virus (MMTV) in Human Breast Cancer—The Value of Bradford Hill Criteria Viruses breast cancer mouse mammary tumour virus causation transmission oncogenic mechanisms virus identification |
| title | Mouse Mammary Tumour Virus (MMTV) in Human Breast Cancer—The Value of Bradford Hill Criteria |
| title_full | Mouse Mammary Tumour Virus (MMTV) in Human Breast Cancer—The Value of Bradford Hill Criteria |
| title_fullStr | Mouse Mammary Tumour Virus (MMTV) in Human Breast Cancer—The Value of Bradford Hill Criteria |
| title_full_unstemmed | Mouse Mammary Tumour Virus (MMTV) in Human Breast Cancer—The Value of Bradford Hill Criteria |
| title_short | Mouse Mammary Tumour Virus (MMTV) in Human Breast Cancer—The Value of Bradford Hill Criteria |
| title_sort | mouse mammary tumour virus mmtv in human breast cancer the value of bradford hill criteria |
| topic | breast cancer mouse mammary tumour virus causation transmission oncogenic mechanisms virus identification |
| url | https://www.mdpi.com/1999-4915/14/4/721 |
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