Clonal Isolation of Different Strains of Mouse Mammary Tumor Virus-Like DNA Sequences from Both the Breast Tumors and Non-Hodgkin’s Lymphomas of Individual Patients Diagnosed with Both Malignancies

Abstract

Purpose: In a previous study, we had detected the presence of mouse mammary tumor virus (MMTV)-like envelope (ENV) gene sequences in both the breast tumors and non-Hodgkin's lymphoma tissue of two of our breast tumor patients who had been diagnosed simultaneously with both malignancies. The aim of this study was to determine if MMTV-like DNA sequences are present in the breast tumors and non-Hodgkin's lymphomas of additional patients suffering from both malignancies and if so to characterize these sequences in detail.Experimental Design: DNA was extracted from formalinfixed, paraffin-embedded tissue sample blocks of breast tumors and non-Hodgkin's lymphomas from patients suffering from both malignancies. A 250-bp region of the MMTV ENV gene and a 630-bp region of the MMTV long terminal repeat (LTR) open reading frame (ORF) that encodes the MMTV superantigen (sag) gene were amplified by PCR from the isolated DNA. Amplified products were analyzed by Southern blotting, cloned, and sequenced.Results: MMTV-like ENV and LTR sequences were detected in both the breast tumors and non-Hodgkin's lymphomas of 6 of 12 patients suffering from both malignancies. A novel mutant of the MMTV ENV gene was identified in these patients. Characterization of the MMTV-like LTR highly variable sag sequences revealed total or nearly total identity to three distinct MMTV proviruses from two different branches of the MMTV phylogenetic tree.Conclusions: The presence of MMTV-like ENV and LTR sequences in both the breast tumors and nonHodgkin's lymphomas of 6 additional patients suggests a possible involvement of these sequences in these two malignancies. MMTV-like LTR sequence homology to different MMTV proviruses revealed the presence of more than one strain of MMTV-like sequences in each individual suggesting the possibility of multiple infections in these patients.

Mouse Mammary Tumor Virus-Like Viral Infection and Human Breast Cancer

“…Elsewhere in this issue, an elaboration of their important observation is published indicating that 6 of 12 patients with both breast cancer and non-Hodgkin's lymphoma had viral sequences in each (21). This extends prior reports that non-Hodgkin's lymphoma is more common in patients with breast cancer than expected if the diseases were randomly distributed (22) and offers a possible explanation.…”

“…Etkind et al (21) sequenced the env sequences from the six breast cancers and six lymphomas and found that each contained a single nucleotide mutation compared with the env sequence from C 3 H MMTV. Only the breast cancers each contained one clone of unmutated sequence (21). This observation might represent two independent infections (the mutant virus was previously seen in a male with non-Hodgkin's lymphoma who did not have breast cancer) or high mutability of this particular strain of HMTV with selective parasitism of lymphoid cells only with the mutant variants.…”

“…The tools of molecular biology similar to those we (6) and Etkind et al (21) have used are appropriate to launch studies in other candidate neoplasms. Fowl, murine, feline, bovine, ape, and new world monkey leukemias are viral in origin (27).…”

Of mice, cats, and men: Is human breast cancer a Zoonosis?

“…Ever since the discovery of the mouse mammary tumor virus (MMTV) (Bittner, 1936(Bittner, , 1948; Staff of the Roscoe B. Jackson Memorial Laboratory in Bar Harbor, 1933), many efforts have been made to build a human BC model based on the mouse mammary tumor model, since MMTV is universally considered to be the etiologic agent in the vast majority of murine mammary cancer. Several independent laboratories Etkind et al, 2000Etkind et al, , 2004Ford et al, 2003Ford et al, , 2004aHolland and Pogo, 2004;Levine et al, 2004;Liu et al, 2001;Mason et al, 2004;Melana et al, 2001Melana et al, , 2002Wang et al, 1995Wang et al, , 1998Wang et al, , 2001Wang et al, , 2004Xu et al, 2003Xu et al, , 2004, but not others Cason, 2004, 2005;Mant et al, 2004a,b;Selmi et al, 2004;Witt et al, 2003), have detected sequences very closely related to MMTV in DNA isolated from human BC tumors. Additional studies suggest that betaretroviruses are present in a much wider range of species than previously known, including rodents, primates, and felines.…”

Identification of the Segments of the Mouse Transferrin Receptor 1 Required for Mouse Mammary Tumor Virus Infection

“…Although utilization of a site on TfR1 that does not interfere with iron uptake probably benefits the ability of MMTV to infect target cells, it has the potential to limit virus species tropism. Recent work by several laboratories indicates that MMTV-like envelope sequences are found integrated in human breast cancer biopsies, but not normal tissue from the same patient (41)(42)(43), and in tissue from patients with primary biliary cirrhosis (44). Additionally, there is a recent report that MMTV can infect human tissue culture cell lines (45).…”