Association of Mouse Mammary Tumor Virus With Human Breast Cancer: Histology, Immunohistochemistry and Polymerase Chain Reaction Analyses

Lawson, James S.; Mazzanti, Chiara Maria; Civita, Prospero; Menicagli, Michele; Ngan, Christopher C.; Whitaker, Noel J.; Hochman, Jacob; Braitbard, Ori; Yosufi, Benafsha; Glenn, Wendy K.

doi:10.3389/fonc.2018.00141

Cited by 17 publications

(19 citation statements)

References 42 publications

(65 reference statements)

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“…Breast cancer is the most frequent cancer diagnosis among females and a leading cause of cancer deaths worldwide [1,2]. Several viruses have been linked with the development of human breast cancer, but none have been established as having a causal etiology [3,4]. One such agent resembles mouse mammary tumor virus (MMTV), a murine betaretrovirus that plays a direct role in the development of breast cancer in mice [5].…”

Section: Introductionmentioning

confidence: 99%

Seroprevalence of Human Betaretrovirus Surface Protein Antibodies in Patients with Breast Cancer and Liver Disease

Zhang

Bashiri

Kneteman

et al. 2020

Journal of Oncology

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Mouse mammary tumor virus (MMTV) is a betaretrovirus that plays a causal role in the development of breast cancer and lymphoma in mice. Closely related sequences that share 91–99% nucleotide identity with MMTV have been repeatedly found in humans with neoplastic and inflammatory diseases. Evidence for infection with a betaretrovirus has been found in patients with breast cancer and primary biliary cholangitis and referred to as the human mammary tumor virus and the human betaretrovirus (HBRV), respectively. Using the gold standard technique of demonstrating retroviral infection, HBRV proviral integrations have been detected in cholangiocytes, lymph nodes, and liver of patients with primary biliary cholangitis. However, the scientific biomedical community has not embraced the hypothesis that MMTV like betaretroviruses may infect humans because reports of viral detection have been inconsistent and robust diagnostic assays are lacking. Specifically, prior serological assays using MMTV proteins have produced divergent results in human disease. Accordingly, a partial HBRV surface (Su) construct was transfected into HEK293 to create an ELISA. The secreted HBRV gp52 Su protein was then used to screen for serological responses in patients with breast cancer and liver disease. A greater proportion of breast cancer patients (n = 98) were found to have serological reactivity to HBRV Su as compared to age- and sex-matched control subjects (10.2% versus 2.0%, P=0.017, OR = 5.6 [1.25–26.3]). Similarly, the frequency of HBRV Su reactivity was higher in patients with primary biliary cholangitis (n = 156) as compared to blood donors (11.5% vs. 3.1%, P=0.0024, OR = 4.09 [1.66–10.1]). While the sensitivity of the HBRV Su ELISA was limited, the assay was highly specific for serologic detection in patients with breast cancer or primary biliary cholangitis, respectively (98.0% [93.1%–99.7%] and 97.0% [93.4%–98.6%]). Additional assays will be required to link immune response to betaretrovirus infection and either breast cancer or primary biliary cholangitis.

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Section: Introductionmentioning

confidence: 99%

Seroprevalence of Human Betaretrovirus Surface Protein Antibodies in Patients with Breast Cancer and Liver Disease

Zhang

Bashiri

Kneteman

et al. 2020

Journal of Oncology

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“…Many MMTV-like positive human breast cancer have similar histology to MMTV positive mouse mammary tumors and MMTV-like infection was frequently identified in benign breast neoplastic tissues [ 35 ]. It has been hypothesized that MMTV-like sequences represent, in humans, an event bound to the early steps of carcinogenesis [ 20 ] and the presence of MMTV-like sequences and antigen in tubulopapillary and WD and locally infiltrative FMCs seems to confirm the role of the virus in the early phase of mammary tumor development also in the feline species, even if an extensive study on pre-neoplastic lesions also in this species could give important confirmations.…”

Section: Discussionmentioning

confidence: 99%

Mouse mammary tumour virus-like env nucleotide and p14 signal peptide are present in feline mammary carcinomas, but not in neoplastic or dysplastic canine mammary lesions

et al. 2018

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Mouse mammary tumour virus-like (MMTV-like) is suspected to be involved in human breast cancer and it has been hypothesized that companion animals might have a role in viral transmission. The aim of our study was to investigate the presence of MMTV-like nucleotide sequences and viral protein in a larger number of feline (FMCs) and canine mammary carcinomas (CMCs) by nested PCR and immunohistochemistry. Results showed that the presence of MMTV-like env sequence in FMCs was 7% (6/86), while all the CMCs and canine dysplastic lesions scored negative. All PCR-positive FMCs scored positive for the MMTV p14 signal peptide of the envelope precursor protein of the virus. In contrast, all PCR-negative FMCs and canine mammary lesions were also negative for immunohistochemistry analysis. Canine and feline normal mammary gland tissues scored negative for both PCR and MMTV-p14 protein. Multiple nucleotide alignment of MMTV-like env gene sequences isolated from cat showed 97% and 99% similarity with HMTV and MMTV, respectively, while the others two presented some polimorphisms. Particularly the sequences of one of these two tumors showed a polymorphism (c.7575 ), that causes a previously unreported amino acid substitution (Thr > Ala). In conclusion, the results of our study showed the presence of MMTV-like sequences and viral protein in some FMCs. Further studies are needed to understand whether this virus does play a role in the development of FMCs, if MMTV-like is an exogenous virus as these data suggest and, in such a case, how and from whom this virus was acquired.

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“…MMTV sequences were identified in only three of over 800 breast cancer specimens from The Cancer Genome Atlas (TCGA) as compared to the frequent identification by PCR techniques of MMTV sequences in over 40% of breast cancers. 21 This low identification of MMTV by whole-genome sequencing is possibly due to its limited integration into the host human genome. There are similar experiences with respect to other retroviruses, including bovine leukemia virus and human immunodeficiency virus.…”

Section: Contaminationmentioning

confidence: 99%

“…While there are correlations between MMTV-like positive human invasive breast cancers and histological characteristics similar to MMTV-positive mouse mammary tumors, there do not appear to be any associations with histological types. 21…”

Section: Epidemiologymentioning

confidence: 99%

Evidence for a causal role by mouse mammary tumour-like virus in human breast cancer

Lawson

Glenn

2019

npj Breast Cancer

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We have reviewed the evidence relevant to mouse mammary tumour viruses (MMTV) and human breast cancer. The prevalence of MMTV-like gene sequences is 15-fold higher in human breast cancer than in normal human breast tissue controls and is present in up to 40% of human breast cancers. MMTV-like gene sequences can be identified in benign breast tissues 1-11 years before the development of positive MMTV-like breast cancer in the same women. The prevalence of MMTV antibodies in sera from women with breast cancer is 5-fold higher than in normal women. MMTV can infect human breast epithelial cells and integrate at random into the human genome located in those cells. MMTV-like gene sequences are present in human milk from normal lactating women and with increased prevalence in milk from women at risk of breast cancer. MMTV-like virus associated human breast cancer has strikingly similar features to MMTV-associated mouse mammary tumours. These features include almost identical nucleotide sequences and structure of the MMTV genome, histology, superantigen expression, MMTV infection of B and T lymphocytes and hormone dependence. MMTV-like gene sequences have also been identified in dogs, cats, monkeys, mice and rats. Saliva has been identified as the most plausible means of transmission from human to human and possibly from dogs to humans. The evidence meets the classic causal criteria. A causal role for MMTV-like viruses in human breast cancer is highly likely.npj Breast Cancer (2019) 5:40 ; https://doi.

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Association of Mouse Mammary Tumor Virus With Human Breast Cancer: Histology, Immunohistochemistry and Polymerase Chain Reaction Analyses

Cited by 17 publications

References 42 publications

Seroprevalence of Human Betaretrovirus Surface Protein Antibodies in Patients with Breast Cancer and Liver Disease

Seroprevalence of Human Betaretrovirus Surface Protein Antibodies in Patients with Breast Cancer and Liver Disease

Mouse mammary tumour virus-like env nucleotide and p14 signal peptide are present in feline mammary carcinomas, but not in neoplastic or dysplastic canine mammary lesions

Evidence for a causal role by mouse mammary tumour-like virus in human breast cancer

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