Investigators have tried to determine the involvement of HMTV in human breast cancers since 1943, when mouse mammary tumour virus (MMTV) was shown to cause mammary cancers in mice [
59]. Several groups established that MMTV-like sequences were present in human breast cancer samples, but absent in normal tissues [
60]. Furthermore, HMTV isolated from primary cultures of breast cancer cells had 95% homology with MMTV. In mice, the HMTV homolog promotes tumour formation through the insertion mutagenesis of Wnt oncogenes, thereby promoting its activation. In a recent study, Wnt-1 expression was higher in specimens which were positive for
env, an envelope protein of MMTV, compared with
env-negative specimens [
61].
Env is typically absent in normal tissues and present in breast cancer tissues in both mice and human. In addition to the Wnt region, the common integration sites for MMTV were found to be in loci 35 that contain regions of the Fgf and Rspo gene families. The sites were frequently activated in tumours induced by MMTV, which primarily caused mammary premalignant hyperplastic outgrowth. Other genes were also deregulated, including Phf19 and Fox1. For example, Phf19 increased cell invasion capability and Fox1 promoted anchorage independent colony formation of MMTV infected cells. Approximately 20 of the HMTV common insertion site-associated genes are deregulated and/or mutated in human breast tumours [
62]. HMTV sequences for
env,
gag, and
sag from patients with ductal carcinoma and mammary hyperplasia have been cloned and sequenced, revealing the viral gene existence. The study hypothesised that the expression of HMTV sequences could be a risk factor for genome instability and for disease development [
63]. Moreover, the localisation of the MMTV
env sequences to the nuclei of human breast cancer cells indicated that the provirus integrated into cancer cells [
61]. These MMTV viral sequences were more common in conditions such as gestational [
64] and familial breast cancers, indicating that a provirus could be transmitted or inherited. In addition, geographic localisation might also play a role in virus distribution. For example, the highest prevalence of viral sequence-positive breast cancer was in Tunisia, a Country known to have the highest prevalence of rapidly progressing inflammatory breast cancer in the world [
65]. Inflammatory breast cancer is a form of breast cancer in which the presence of viral sequences are found to be associated with tumour aggressiveness in patients [
66]. When the investigators examined samples from patients with both diseases, they found viral sequences in breast tissues as well as in lymphoma tissues.
Cells infected with MMTV, like many other cancer cells, have highly active Src kinase. MMTV expressing cells escape apoptosis by activation of immune receptor tyrosine kinase-based activation motif-mediated Src tyrosine kinase signalling pathways [
67]. EBV (68%), HPV (50%) and MMTV (78%) gene sequences are present and co-exist in many human breast cancers. Normal controls showed these viruses were also present in epithelial cells in human milk with less occurrence compared to breast cancer cells. The presence of these viruses in breast cancer is associated with younger age of diagnosis and possibly an increased grade of breast cancer [
68]. These findings provide further evidence for a potential role of HMTV in breast cancer, but needs to be further investigated.