Abstract
Mouse mammary tumor virus (MMTV) is a betaretrovirus that plays a causal role in the development of breast cancer and lymphoma in mice. Closely related sequences that share 91–99% nucleotide identity with MMTV have been repeatedly found in humans with neoplastic and inflammatory diseases. Evidence for infection with a betaretrovirus has been found in patients with breast cancer and primary biliary cholangitis and referred to as the human mammary tumor virus and the human betaretrovirus (HBRV), respectively. Using the gold standard technique of demonstrating retroviral infection, HBRV proviral integrations have been detected in cholangiocytes, lymph nodes, and liver of patients with primary biliary cholangitis. However, the scientific biomedical community has not embraced the hypothesis that MMTV like betaretroviruses may infect humans because reports of viral detection have been inconsistent and robust diagnostic assays are lacking. Specifically, prior serological assays using MMTV proteins have produced divergent results in human disease. Accordingly, a partial HBRV surface (Su) construct was transfected into HEK293 to create an ELISA. The secreted HBRV gp52 Su protein was then used to screen for serological responses in patients with breast cancer and liver disease. A greater proportion of breast cancer patients (n = 98) were found to have serological reactivity to HBRV Su as compared to age- and sex-matched control subjects (10.2% versus 2.0%, P=0.017, OR = 5.6 [1.25–26.3]). Similarly, the frequency of HBRV Su reactivity was higher in patients with primary biliary cholangitis (n = 156) as compared to blood donors (11.5% vs. 3.1%, P=0.0024, OR = 4.09 [1.66–10.1]). While the sensitivity of the HBRV Su ELISA was limited, the assay was highly specific for serologic detection in patients with breast cancer or primary biliary cholangitis, respectively (98.0% [93.1%–99.7%] and 97.0% [93.4%–98.6%]). Additional assays will be required to link immune response to betaretrovirus infection and either breast cancer or primary biliary cholangitis.
Highlights
Breast cancer is the most frequent cancer diagnosis among females and a leading cause of cancer deaths worldwide [1, 2]
Using the pCMV-Su-TAP construct, very little human betaretrovirus (HBRV) Su protein was detected in lysates from transfected HEK293T cells
300 ml was obtained for each batch, which was purified with chromatography to derive 150–200 μg HBRV Su protein
Summary
Breast cancer is the most frequent cancer diagnosis among females and a leading cause of cancer deaths worldwide [1, 2]. Several viruses have been linked with the development of human breast cancer, but none have been established as having a causal etiology [3, 4]. One such agent resembles mouse mammary tumor virus (MMTV), a murine betaretrovirus that plays a direct role in the development of breast cancer in mice [5]. E viral burden is below the limits of detection in blood, and the agent is encoded as an endogenous retrovirus in most mice; exogenous viral genomic nucleic acid sequences cannot be distinguished from the endogenous expression of MMTV [12]. A diagnosis of MMTV infection is made by assessing the skewing of T-cell receptor V-β subsets to demonstrate the MMTV superantigen effect [14]
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