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

Hsiao-Huei Chen,Alexandre F R Stewart

doi:10.3390/v14030559

Hsiao-Huei Chen, Alexandre F R Stewart

Open Access

https://doi.org/10.3390/v14030559

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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.

Highlights

Environmental factors play an important part in the etiology of sporadic breast cancer [1]
Genome-wide association studies to identify common genetic variants associated with the risk of breast cancer have relied predominantly on cohorts residing in the United States, Canada, Australia and Western Europe, regions with high breast cancer incidence [11,12]
We proposed that mammary tumor virus (MMTV) might be transmitted to humans from house mice, from the Western European house mouse Mus musculus domesticus, and account for the geographic variation in breast cancer incidence [16]

Summary

Introduction

Environmental factors play an important part in the etiology of sporadic breast cancer [1]. Geographic variation in human breast cancer incidence is well-recognized, and the country of residence accounts for ~80% of the lifetime risk [2]. Environmental factors endemic to regions of high breast cancer incidence remain to be identified. While up to 20% of breast cancer risk occurs in families [9,10], families tend to remain in specific geographic areas and share environmental as well as genetic factors. Since many studies are conducted in the United States, a country with one of the highest incidences of breast cancer, the genetic contribution to breast cancer risk may be overestimated (and include the geographic environmental factor). Genome-wide association studies to identify common genetic variants associated with the risk of breast cancer have relied predominantly on cohorts residing in the United States, Canada, Australia and Western Europe, regions with high breast cancer incidence [11,12]. For the 77 most common genetic variants for breast cancer, women carrying most of these variants had a lifetime risk of breast cancer increased by less than 8% [13], highlighting the limited contribution of genetic risk to breast cancer

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