A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers

Braitbard, Ori; Roniger, Maayan; Bar-Sinai, Allan; Rajchman, Dana; Gross, Tamar; Abramovitch, Hillel; Ferla, Marco La; Franceschi, Sara; Lessi, Francesca; Naccarato, Antonio Giuseppe; Mazzanti, Chiara Maria; Bevilacqua, Generoso; Hochman, Jacob

doi:10.18632/oncotarget.7762

Cited by 16 publications

(17 citation statements)

References 44 publications

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“…We previously found that only low nM plasma levels of hPEPD-G278D or hPEPD could be achieved in mice after injecting them, but EP markedly elevated their plasma levels [14]. We subsequently found that EP inhibits their degradation by a plasma proteolysis pathway composed of coagulation proteases [33]. Although EP itself shows no effect on ErbB2 signaling and tumor growth in several mouse tumor models [14], it was not previously evaluated in A431 tumors in vivo.…”

Section: Resultsmentioning

confidence: 99%

Dual inhibition of ErbB1 and ErbB2 in cancer by recombinant human prolidase mutant hPEPD-G278D

Yang

Bhattacharya

et al. 2016

Oncotarget

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ErbB1 and ErbB2 are oncogenic cell surface receptor tyrosine kinases, linked to many forms of human cancer, and are major cancer therapeutic targets. Many lines of evidence indicate that targeting ErbB1 and ErbB2 is an important cancer therapeutic approach. We recently found that a recombinant enzymatically-inactive mutant of human prolidase, i.e., hPEPD-G278D, is an inhibitory ligand of ErbB2 and strongly inhibits ErbB2-overexpressing cells in vitro and in vivo. hPEPD-G278D also binds to ErbB1. Here, we show that hPEPD-G278D binds to ErbB1 with high affinity, initially activating ErbB1 but later silencing it, and that deletion of subdomain 2 in ErbB1 extracellular domain abolishes the binding. The proliferation of ErbB1-overexpressing cells is strongly inhibited by hPEPD-G278D, regardless of ErbB2 expression or cell type, whereas cells lacking ErbB1 and ErbB2 are insensitive to it. In contrast, EGF, another ErbB1 ligand, either stimulates or mildly inhibits cell proliferation. Moreover, hPEPD-G278D treatment of mice bearing ErbB1-overexpressing tumors leads to tumor regression, which is accompanied by down regulation and decreased phosphorylation of ErbB1 and ErbB2 as well as decreased phosphorylation of downstream signaling molecules and activation of apoptosis in the tumor tissues. We conclude that hPEPD-G278D is a dual inhibitor of ErbB1 and ErbB2 and selectively targets cancer cells overexpressing ErbB1 and/or ErbB2. Moreover, our finding that both receptors are silenced in cancer cells by hPEPD-G278D highlights an unusual consequence of ligand-receptor interaction.

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Section: Resultsmentioning

confidence: 99%

Dual inhibition of ErbB1 and ErbB2 in cancer by recombinant human prolidase mutant hPEPD-G278D

Yang

Bhattacharya

et al. 2016

Oncotarget

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“…The effectiveness of these vaccines is convincing evidence that MMTV is causal in MMTV-associated mouse mammary tumors. Recently, the Hochman group working in Israel, together with the Bevilacqua group in Italy, have identified the MMTV envelope protein as a target for both prevention and treatment of MMTV-associated breast and other cancers ( 198 ).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein–Barr Virus (EBV)

Salmons²,

2018

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BackgroundAlthough the risk factors for breast cancer are well established, namely female gender, early menarche and late menopause plus the protective influence of early pregnancy, the underlying causes of breast cancer remain unknown. The development of substantial recent evidence indicates that a handful of viruses may have a role in breast cancer. These viruses are mouse mammary tumor virus (MMTV), bovine leukemia virus (BLV), human papilloma viruses (HPVs), and Epstein–Barr virus (EBV-also known as human herpes virus type 4). Each of these viruses has documented oncogenic potential. The aim of this review is to inform the scientific and general community about this recent evidence.The evidenceMMTV and human breast cancer—the evidence is detailed and comprehensive but cannot be regarded as conclusive. BLV and human breast cancer—the evidence is limited. However, in view of the emerging information about BLV in human breast cancer, it is prudent to encourage the elimination of BLV in cattle, particularly in the dairy industry. HPVs and breast cancer—the evidence is substantial but not conclusive. The availability of effective preventive vaccines is a major advantage and their use should be encouraged. EBV and breast cancer—the evidence is also substantial but not conclusive. Currently, there are no practical means of either prevention or treatment. Although there is evidence of genetic predisposition, and cancer in general is a culmination of events, there is no evidence that inherited genetic traits are causal.ConclusionThe influence of oncogenic viruses is currently the major plausible hypothesis for a direct cause of human breast cancer.

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“…At the same time, the low percentage of MMTV positivity (8.7%) found in this study could not alone explain the pattern of breast cancer in this area and other studies are needed to further explore the role of the MMTV in breast cancer. Interestingly, a recent study showed that priming mice with the MMTV-p14 signal peptide elicits a protective immune response against MMTV induced tumor and the use of anti-p14 antibodies or the T-cells from p14-immunized mice is an effective therapeutic intervention [ 42 ]. This study provides a promising approach for prevention and treatment of MMTV-associated human tumors.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Mouse Mammary Tumor Virus (MMTV)-like sequences in human breast cancer tissues and adjacent normal breast tissues in Saudi Arabia

2018

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BackgroundBreast cancer is considered the most common cancer in women worldwide and is the leading cause of cancer mortality. Sequences similar to Mouse Mammary Tumor Virus (MMTV) were detected in human breast cancer in several studies from different geographical areas. However, the role played by this virus in breast cancer tumorigenesis is not completely understood. These MMTV-like sequences were found to be associated with breast cancer of more malignant types. The aim of this study is to determine the prevalence of MMTV-like envelope gene (env) positivity in breast cancer and non-cancerous breast tissue from Saudi Arabia.MethodsDetection of MMTV-like env proviral sequences was done using newly designed primers for conventional polymerase chain reaction (PCR). One hundred nighty four samples were collected from 103 females with breast cancer in addition to 51 control breast tissue obtained from individuals without cancer. We additionally investigated the association of proviral positivity with age of the patients, grade of breast cancer and presence of lymph node metastasis. The results were confirmed by sequencing.ResultsThe prevalence of MMTV-like env proviral positivity was 8.7% (9/103). MMTV env proviral sequences were detected in 5.9% (6/101) of breast cancer tissues and 9.7% (9/93) of non-cancerous adjacent tissues obtained from the same patients. None of the 51 control sample showed positive result for the MMTV env gene. No significant association was found between detection of the virus and the age of the patient, grade of the cancer or presence of metastasis.ConclusionWe document the presence of low frequency of MMTV env provirus sequence among breast cancer patients from Saudi Arabia. Further studies are needed to explore the role of the MMTV in breast cancer.

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A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers

Cited by 16 publications

References 44 publications

Dual inhibition of ErbB1 and ErbB2 in cancer by recombinant human prolidase mutant hPEPD-G278D

Dual inhibition of ErbB1 and ErbB2 in cancer by recombinant human prolidase mutant hPEPD-G278D

Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein–Barr Virus (EBV)

Prevalence of Mouse Mammary Tumor Virus (MMTV)-like sequences in human breast cancer tissues and adjacent normal breast tissues in Saudi Arabia

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