Variable Transcriptional Activity of Endogenous Retroviruses in Human Breast Cancer

Abstract

Human endogenous retroviruses (HERVs) account for up to 9% of the human genome and include more than 800 elements related to betaretroviruses. While mouse mammary tumor virus (MMTV) is the accepted etiological agent of mammary tumors in mice, the role of retroviral elements in human breast cancer remains elusive. Here, we performed a comprehensive microarray-based analysis of overall retroviral transcriptional activities in 46 mammary gland tissue specimens representing pairs of nonmalignant and tumor samples from 23 patients. An analysis of nonmalignant tissue samples revealed a distinct, mammary gland-specific HERV expression profile that consists of 18 constitutively active HERV taxa. For corresponding tumor samples, a general trend toward lower levels of HERV transcription was observed, suggesting common regulatory mechanisms. In various subsets of patients, however, increased transcript levels of single class I HERV families (HERV-T, HERV-E, and HERV-F) and several class II families, including HML-6, were detected. An analysis of transcribed HML-6 sequences revealed either the activation of some or the increased activity of several proviral loci. No evidence for MMTV or human MMTV-like virus transcripts was found, indicating that transcriptionally active, MMTV analogous, exogenous viruses were not present in the breast cancer samples analyzed.Great efforts have been invested in searching for the etiology of human breast cancer, a malignancy accounting for one-fifth of all female cancers worldwide. Although many studies have identified several risk factors, such as age, diet, hormonal balance, and genetic predisposition, a clear underlying cause for the disease, especially for sporadic cases of breast cancer, remains unknown. The current data suggest that breast cancer most likely is a multifactorial disease encompassing many different causes and factors (2, 30). Moreover, it has been suggested that an infectious agent contributes to the development of human breast cancer (16,45). Of note, a novel human retrovirus (xenotropic murine leukemia virus) has recently been associated with human prostate cancer (7, 48).Since type B mouse mammary tumor virus (MMTV) is the major etiological agent of mammary gland neoplasia in laboratory mice, researchers have searched extensively for a related human retrovirus that could be responsible for human breast cancer. The existence of such a virus, although postulated for many years, has not been conclusively demonstrated, although a long line of indirect evidence for it exists. This evidence is reflected by reports on the expression of type B envelope glycoprotein (gp52) (32) and the occurrence of virus-like particles in breast cancer biopsy specimens (8), in milk (38), and in cultures of breast cancer-derived cell lines (20, 40) as well as the detection of antibodies directed against gp52 in breast cancer patients (52). However, supporting observations have been confounded by a failure to continually observe virus particles in human tumors and by numerous controversial repo...

Lack of Detection of the Mouse Mammary Tumor-like Virus (MMTV) Env Gene in Iranian Women Breast Cancer using Real Time PCR

“…Findings of Brindra et al (2007) in Swedish women and Frank et al (2008) in German women also support our results. However, Ford CE et al detected very low ratio of MMTV DNA in Vietnamese and Vietnamese-Australian women (0.8% and 0% respectively) using PCR method (Ford et al, 2003).…”

“…A highly variable reports are available on the present of MMTV-like virus in female breast tumor ranging from 78.8% in Australia (Ford et al, 2004) to no virus (0%) in Japan (Fukuoka et al, 2008) and Germany (Frank et al, 2008). this results implies that geographic and ethnic variations may play an important role in MMTV-like virus infection and its role on breast cancer development.…”

Evolutionary diversification of DYX1C1 transcripts via an HERV-H LTR integration event

“…Additionally, HERV insertions can modify the expression of nearby genes by altering promoter activity, providing poly-A signals, or donating alternative splice sites. One interesting example, the HERV-K element, has fulllength intact ORFs, and their remnants and proteins have been detected in breast cancer (Frank et al, 2008;Golan et al, 2008;Wang-Johanning et al, 2008), and testis cancer (Goedert et al, 1999;Ruprecht et al, 2008). Our data adds to the mounting evidence of HERV-associated gene expression alteration by showing that an HERV-H LTR insertion affects the expression of the DYX1C1 gene by providing a poly-A signal.…”

HIV-1 Infection Leads to Increased Transcription of Human Endogenous Retrovirus HERV-K (HML-2) ProvirusesIn Vivobut Not to Increased Virion Production

“…Since then, HERV-K expression has been observed in a variety of human diseases, most notably in different types of cancer and autoimmune disease (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). While these results are suggestive, conclusive evidence for a causal association of HERV-K with any human disease has yet to be obtained.…”