Viral infections and breast cancer – A current perspective

Highlights

• Conflicting reports about the role of infectious agents in the human breast cancer.

• Recent next generation sequencing studies do not detect viruses in breast cancer.

• Comprehensive review of past literature (pre next-gen sequencing).

• Comprehensive review of modern literature (next-gen sequencing pathogen detection).

• Concludes that modern technology does not support viral aetiology in breast cancer.

Abstract

Sporadic human breast cancer is the most common cancer to afflict women. Since the discovery, decades ago, of the oncogenic mouse mammary tumour virus, there has been significant interest in the potential aetiologic role of infectious agents in sporadic human breast cancer. To address this, many studies have examined the presence of viruses (e.g. papillomaviruses, herpes viruses and retroviruses), endogenous retroviruses and more recently, microbes, as a means of implicating them in the aetiology of human breast cancer. Such studies have generated conflicting experimental and clinical reports of the role of infection in breast cancer. This review evaluates the current evidence for a productive oncogenic viral infection in human breast cancer, with a focus on the integration of sensitive and specific next generation sequencing technologies with pathogen discovery. Collectively, the majority of the recent literature using the more powerful next generation sequencing technologies fail to support an oncogenic viral infection being involved in disease causality in breast cancer. In balance, the weight of the current experimental evidence supports the conclusion that viral infection is unlikely to play a significant role in the aetiology of breast cancer.

Introduction

Breast cancer is the most common cancer to afflict women and accounts for approximately one quarter of all female cancers [1]. However, most breast cancers are sporadic and efforts to identify a unifying genetic or epigenetic cause can only explain a small proportion of disease. For instance, genetic variants which predispose to disease are present in approximately 30% of cases [2]. Intriguingly, in Queensland, Australia, the incidence of breast cancer increased from 80/100 000 in 1983 to 117/100 000 in 2002; equivalent to a 45% increase in incidence [3]. Similarly, in the United States of America, there was a 40% increase in the incidence over the 25 years to 2002 [4]. This increase in incidence may be linked to environmental factors that contribute to breast cancer development as exemplified by the increased incidence of breast cancer in Japanese women who migrated to the USA [5,6]. There are also accounts of ‘cancer clusters’ where high incidences of breast cancer are reported in work sites and amongst spouses [7,8]. Some of the increase in disease may be however linked to factors such as increased incidence of obesity [9]. Nonetheless, these observations have fuelled interest in a potential infectious aetiology for breast cancer.

Globally, it is estimated that 16% of all human cancers have an infectious origin [10]. Oncogenesis can be induced i) directly by viral genes, such as high-risk Human Papilloma Virus in cervical and mucosal head and neck cancer, ii) by viruses which reduce host immunity such as human immunodeficiency virus, and iii) by viruses which induce oncogenesis via chronic inflammation such as hepatitis B and C. Indeed, in 1936, it was observed that a transmissible form of mammary tumours in the mouse was caused by an extrachromosomal factor transmitted in breast milk [11], later identified as ‘Mouse Mammary Tumour Virus (MMTV)’ [12]. In all of these instances, tumours were associated with a high viral load which made virus discovery and analysis relatively simple.

Many different infectious agents have been investigated as potential carcinogenic agents in breast cancer, including Human Papilloma Viruses (HPV), MMTV and Epstein-Barr virus (EBV) [13]. However, significant controversy exists in the literature as to the possible role of infection with viruses or other pathogens in human breast cancer. This controversy has been fuelled by the ultralow abundance of viral DNA within the tissue. Furthermore, published reports which investigate the presence of virus in breast tissue vary vastly with respect to the nature of pre-analytical phase (e.g. sample type, nature of storage, sample preparation, laboratory practices) and analytical aspects (e.g. detection method, PCR or probe design, use of controls). This raises the fundamental issue of the most appropriate molecular techniques with which to detect the viruses. The debate which surrounds the putative association of viruses with breast cancer has become more polarised with the now standard use of next generation sequencing technologies.

This review will examine the evidence for viral infection as a causative agent in breast cancer and will reference both standard molecular biology techniques in addition to next generation sequencing data. Whilst breast cancer treatment has evolved significantly over the last 30 years, the identification of markers, events or indeed infection associated with disease could be exploited to develop new treatments or induce cures in patients. For this reason, it is important that a unifying rationale toward the analysis and design of pathogen-disease studies; in particular next-generation sequencing data, is used to guide sensible diagnostic and therapeutic interventions in the future.