Revisiting the MMTV Zoonotic Hypothesis to Account for Geographic Variation in Breast Cancer Incidence

Abstract

Human breast cancer incidence varies by geographic location. More than 20 years ago, we proposed that zoonotic transmission of the mouse mammary tumor virus (MMTV) from the western European house mouse, Mus musculus domesticus, might account for the regional differences in breast cancer incidence. In the intervening years, several developments provide additional support for this hypothesis, including the limited impact of genetic factors for breast cancer susceptibility revealed by genome-wide association studies and the strong effect of antiretroviral therapy to reduce breast cancer incidence. At the same time, economic globalization has further expanded the distribution of M. m. domesticus to Asia, leading to a significant increase in breast cancer incidence in this region. Here, we revisit this evidence and provide an update to the MMTV zoonotic hypothesis for human breast cancer at a time when the world is recovering from the global COVID-19 zoonotic pandemic. We present evidence that mouse population outbreaks are correlated with spikes in breast cancer incidence in Australia and New Zealand and that globalization has increased the range of M. m. domesticus and MMTV. Given the success of global vaccination campaigns for HPV to eradicate cervical cancer, a similar strategy for MMTV may be warranted. Until breast cancer incidence is reduced by such an approach, zoonotic transmission of MMTV from mice to humans as an etiologic factor for breast cancer will remain controversial.

Mouse Mammary Tumor Virus (MMTV) and MMTV-like Viruses: An In-depth Look at a Controversial Issue

“…The Authors correlated the high copy numbers of endogenous Mtv in murine species with the potential of generating exogenous, infectious virions by recombination between different Mtvs , as clearly demonstrated in an experimental setting by Golovkina et al [ 128 , 129 ]. In 2004, Levine et al [ 130 ] came to the same conclusion as Stewart et al [ 126 , 127 ] by showing that there was a significantly similar geographic prevalence of MMTVels in humans and MMTV in wild mice. A recent study by Wang et al, in China, found similar evidence, showing that the difference in the prevalence of MMTV-like virus in BC samples from northern (23%) and southern China (6%) could be dependent on the distribution of M. domesticus , M. musculus , and M. castaneus [ 131 ].…”

“…Several environmental risk factors have been proposed for human sporadic BC, in addition to the presence of MMTV-like sequences. Strikingly, as already discussed, high incidence of human BC has been found to correlate with the predominant presence of a particular mouse strain [ 126 , 127 ]. Based on this correlation, transmission of MMTV from this mouse strain to man was proposed [ 126 , 127 ].…”

“…Strikingly, as already discussed, high incidence of human BC has been found to correlate with the predominant presence of a particular mouse strain [ 126 , 127 ]. Based on this correlation, transmission of MMTV from this mouse strain to man was proposed [ 126 , 127 ]. However, if we accept that mice can transmit MMTV to humans, there appears to be a missing link that may be represented by pets such as dogs and cats [ 10 , 11 , 12 , 13 , 15 , 176 ].…”

“…Additional observations supporting this thesis are the reports of cases of MMTV-exposed laboratory workers with immune reactivity to the virus [ 124 ] and a case of seroconversion with the development of an invasive ductal BC [ 125 ]. Interestingly, Stewart et al also observed that the incidence of human BC was highest in areas where Mus domesticus was the resident species of house mouse [ 126 , 127 ]. This evidence suggests that a high frequency of Mus domesticus could be related to increased incidence of HMTV, thus supporting that the virus could be introduced into the human population by mice.…”

“…BC clearly has a multifactorial etiology. The attempt to correlate the incidence of human BC with socioeconomic and geographic parameters has yielded contradictory conclusions [ 126 , 127 , 169 , 170 , 171 ]. Because the prevalence of MMTV-like sequences in humans varies between different ethnic groups [ 8 , 105 , 139 , 172 , 173 , 174 ], the model of an infectious exogenous agent combined with immunogenetic factors in the etiology of BC would fit best [ 175 ].…”