Mouse mammary tumor virus (MMTV) - like exogenous sequences are associated with sporadic but not hereditary human breast carcinoma

Antonio Giuseppe Naccarato,Francesca Lessi,Katia Zavaglia,Maria Adelaide Caligo,Cristian Scatena,Paolo Aretini,Michele Menicagli,Generoso Bevilacqua,Matteo Ghilli,Manuela Roncella,Chiara Maria Mazzanti,Mohammad A Al Hamad

doi:10.18632/aging.102252

Antonio Giuseppe Naccarato, Francesca Lessi + Show 10 more

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https://doi.org/10.18632/aging.102252

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Abstract

The inheritance of mutated suppressor genes, such as BRCA1 and BRCA2, is acknowledged as an etiological factor in hereditary breast carcinoma (HBC). Two different molecular mechanisms are possible; the Knudson’s “two hits” or the gene haploinsufficiency. Etiology of sporadic breast carcinoma (SBC) is not known, although data support the possible role of the betaretrovirus Mouse Mammary Tumor Virus (MMTV). This study analyzes the presence of MMTV exogenous sequences in two representative groups of HBC and SBC, excluding any contamination by murine and retroviral material and endogenous betaretroviruses. The 30.3% of 56 SBC contained MMTV sequences, against the 4.2% of 47 HBC (p < 0.001). Cases positive for viral sequences showed the presence of p14, signal peptide of the MMTV envelope precursor. This result was expected based on the fact that HBCs, having a specific genetic etiology, do not need the action of a carcinogenetic viral agent. Moreover, the striking results obtained by comparing two groups of vastly different tumors represent an additional element of quality control: the distinction between HBC and SBC is so well-defined that results cannot be ascribed to mere coincidence. This paper strengthens the hypothesis for a viral etiology for human sporadic breast carcinoma.

Highlights

Human breast carcinoma (BC) is divided into two wide groups, sporadic (SBC) and hereditary (HBC), each characterized by distinctly different biomolecular pathways and clinical behavior.The etiology of sporadic breast carcinoma (SBC) remains unknown, despite its high frequency and the decades of extensive studies performed worldwide.Recent evidence indicates a close relationship between SBC and the mouse mammary tumor virus (MMTV) [1], a betaretrovirus recognized as the etiological agent of murine mammary tumors [2]
Two different groups of infiltrating breast carcinoma were analyzed for MMTV env-like www.aging-us.com sequences (MMTVels), 47 hereditary breast carcinoma (HBC) and 56 SBC
(80% of cases) [15]; b) primary cultures of HBC can produce Mammary Tumor Virus (MMTV)-like particles [16]; c) MMTV is able to infect in vitro human cells of different types including breast cells [17,18,19], leading to a rapid spread of the virus [20]; e) polypyrimidine tractbinding (PTB) protein, involved in maintaining human breast cancer cell growth and malignant properties, is able to bind the 5’ untranslated region of MMTV mRNA and to stimulate cap-independent translation initiation [21, 22]; f) MMTVels were identified in breast tissues prior to the development of MMTVelspositive breast cancer [23]; and g) MMTV env sequences are absent in the human genome, whereas present in breast tumors and in normal breast tissues [24]

Summary

Introduction

Human breast carcinoma (BC) is divided into two wide groups, sporadic (SBC) and hereditary (HBC), each characterized by distinctly different biomolecular pathways and clinical behavior.The etiology of SBC remains unknown, despite its high frequency (approximately 90% of all cases of BC) and the decades of extensive studies performed worldwide.Recent evidence indicates a close relationship between SBC and the mouse mammary tumor virus (MMTV) [1], a betaretrovirus recognized as the etiological agent of murine mammary tumors [2]. HBCs represent 5-10% of all cases of breast carcinoma They are induced by highly penetrant pathogenic mutations affecting a group of tumor suppressor genes (TSG), transmitted in an autosomal dominant way from one parent. There are cases in which the second mutation cannot be demonstrated To explain this discrepancy, a great deal of attention has been given to the status of the protein coded by TSG. This applies to hereditary tumors the concept of haploinsufficiency, which is a known causative mechanism of nonneoplastic diseases [6]. BRCA1 haploinsufficiency is unique to normal human breast epithelium, explaining why neoplastic transformation in hereditary breast tumors is limited to the mammary gland in most cases [8, 9]. The inherited mutated TSG can be considered an etiological factor for HBC

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