Abstract
Human cytomegalovirus is being recognized as a potential oncovirus beside its oncomodulation role. We previously isolated two clinical isolates, HCMV-DB (KT959235) and HCMV-BL (MW980585), which in primary human mammary epithelial cells promoted oncogenic molecular pathways, established anchorage-independent growth in vitro, and produced tumorigenicity in mice models, therefore named high-risk oncogenic strains. In contrast, other clinical HCMV strains such as HCMV-FS, KM, and SC did not trigger such traits, therefore named low-risk oncogenic strains. In this study, we compared high-risk oncogenic HCMV-DB and BL strains (high-risk) with low-risk oncogenic strains HCMV-FS, KM, and SC (low-risk) additionally to the prototypic HCMV-TB40/E, knowing that all strains infect HMECs in vitro. Numerous pro-oncogenic features including enhanced expression of oncogenes, cell survival, proliferation, and epithelial-mesenchymal transition genes were observed with HCMV-BL. In vitro, mammosphere formation was observed only in high-risk strains. HCMV-TB40/E showed an intermediate transcriptome landscape with limited mammosphere formation. Since we observed that Ki67 gene expression allows us to discriminate between high and low-risk HCMV strains in vitro, we further tested its expression in vivo. Among HCMV-positive breast cancer biopsies, we only detected high expression of the Ki67 gene in basal tumors which may correspond to the presence of high-risk HCMV strains within tumors. Altogether, the transcriptome of HMECs infected with HCMV clinical isolates displays an “oncogenic gradient” where high-risk strains specifically induce a prooncogenic environment which might participate in breast cancer development.
Highlights
Breast cancer is the most common cancer diagnosed among women and recognized as one of the main causes of death in women [1]
The phylogenetic analysis showed that Human cytomegalovirus (HCMV)-BL is close to HCMV-DB, and HCMV-TB40/E is close to the genomes of HCMV-Davis (Supplementary Figure 1)
We assessed the replication of six HCMV clinical isolates in human mammary epithelial cells (HMECs), namely the HCMV-BL and HCMV-DB high-risk strains, the HCMV-FS, HCMV-KM and HCMV-SC low-risk strains, and the prototypic TB40/E strain [20, 21, 29]
Summary
Breast cancer is the most common cancer diagnosed among women and recognized as one of the main causes of death in women [1]. Etiologic factors of breast cancer are classified into genetic and environmental risk factors [2], and among these latter viruses could be involved [3, 4]. The DNA and gene products of several viruses have been identified in breast cancer biopsies [5]. Human cytomegalovirus (HCMV), a ubiquitous pathogen belonging to the Herpesviridae family, High or Low-Risk Oncogenic HCMV has been detected in 90% of early and metastatic breast cancers [6–8]. HCMV DNA or antigens have been found in other malignancies including brain (glioblastoma, medulloblastoma), colon, prostate, and liver [7, 9–13]. HCMV causes asymptomatic to mild infection in immunocompetent host, but it can lead to serious complications in the immunocompromised host and cancer patients [14, 15]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have