Investigation of Oncogenic Potential of Mouse Mammary Tumor Virus (MMTV) in Breast Cancer

Abstract

Breast cancer is the mostly affecting women and is the most common cause of women death globally. In Asia, Pakistan is considered as having very high breast cancer incidence rate which is increasing every year by 19.33%. Numerous studies proposed oncogenic viruses can cause breast cancer, but the proposal is still debatable. Research from past decade has linked viral infection to breast cancer development. This study was aimed to identify the prevalence of endogenouse MMTV sequences and investigate potential pathogenesis of exogenous MMTV virus with host restriction factor (BST-2) in breast cancer development and progression. To identify MMTV prevalence, qualitative PCR technique was used, and DNA samples of breast cancer tissues were screened for MMTV prevalence using specific detection primers. Our results conclude that of 29.3% of breast cancer samples (n=250) were positive for the presence of MMTV sequences with no detection of MMTV in healthy control samples. Also, the statistical analysis showed no association of MMTV prevalence with the breast cancer disease outcomes except for age and grade of breast cancer patients. The restriction factor BST-2/tetherin plays a critical role in preventing the release of MMTV progeny virions from infected cells and in promoting viral clearance through activation of signal transduction pathways. Although BST-2-mediated effect limits cell-free virus infection and spread, what happens to the infected cells ladened with unreleased virions is yet to be determined in breast cancer. To further investigate that BST-2-tethered MMTV virus particles may change molecular signature of infected cells that results in cell-to cell viral spread. Using acute retrovirus infection model and various cell lines (NMuMG, 4T1, HMLE and MDA-231), it showed that titer of extracellular MMTV virus significantly increases while intracellular viral load decreases in BST-2 suppressed cells. Despite equivalent starting cell numbers, BST-2-expressing MMTV infected cells exhibit increased proteolytic and non-proteolytic cell motility. The motile MMTV infected cells contain high levels of viral nucleic acids, BST-2, and metalloproteases. Interestingly, increased cell motility of BST-2-expressing cells correlates with increased infection of target cells in a trans-infection model of virus transmission as well as high activity of metalloproteases. Our findings suggest that in MMTV infection, depends on BST-2 expression to alter the anti-MMTV effect of BST 2 through NF-κB activation that leads to increased MMP-9 secretion. It is concluded that MMTV infected BST-2 expressing cancer cells promote metastasis by enhancing the ability of virus-ladened cells to migrate, carve through extracellular membranes, and infect a population of target cells at distal sites by colony formation and resistance to anoikis. The direct impact of this study will be on women suffering from breast cancer. Spreading awareness via public health sectors regarding Mouse Mammary Tumor Virus screening and link to breast cancer, will aid in the preventive measures against breast cancer.