Oncogenic and Stemness Signatures of the High-Risk HCMV Strains in Breast Cancer Progression

Abstract

Background: Human cytomegalovirus (HCMV) oncomodulation, molecular mechanisms, and ability to support polyploid giant cancer cells (PGCCs) generation might underscore its contribution to oncogenesis, especially breast cancers. The heterogeneity of strains can be linked to distinct properties influencing the virus-transforming potential, cancer types induced, and patient’s clinical outcomes. Methods: We evaluated the transforming potential in vitro and assessed the acquired cellular phenotype, genetic and molecular features, and stimulation of stemness of HCMV strains, B544 and B693, isolated from EZH2HighMycHigh triple-negative breast cancer (TNBC) biopsies. Therapeutic response assessment after paclitaxel (PTX) and ganciclovir (GCV) treatment was conducted in addition to the molecular characterization of the tumor microenvironment (TME). Findings: HCMV-B544 and B693 transformed human mammary epithelial cells (HMECs). We detected multinucleated and lipid droplet-filled PGCCs harboring HCMV. Colony formation was detected and Myc was overexpressed in CMV-Transformed-HMECs (CTH cells). CTH-B544 and B693 stimulated stemness and established an epithelial/mesenchymal hybrid state. HCMV-IE1 was detected in CTH long-term cultures indicating a sustained viral replication. Biopsy B693 unveiled a tumor signature predicting a poor prognosis. CTH-B544 cells were shown to be more sensitive to PTX/GCV therapy. Conclusion: The oncogenic and stemness signatures of HCMV strains accentuate the oncogenic potential of HCMV in breast cancer progression thereby leading the way for targeted therapies and innovative clinical interventions that will improve the overall survival of breast cancer patients.

Human Cytomegalovirus Protein Expression Is Correlated with Shorter Overall Survival in Breast Cancer Patients: A Cohort Study

“…In this study, we found that higher HCMV protein expression in breast cancer biopsies at the time of primary diagnosis is significantly associated with a shorter overall survival in patients with breast cancer. Our data provides an important clinical validation to the numerous in vitro and in vivo studies demonstrating that HCMV could play a role in breast cancer pathogenesis [ 11 , 54 , 55 , 56 , 57 , 58 , 71 , 72 ]. These observations were derived from histological analyses performed on a cohort of tissue stained with an automated technique that could be easily applied by others for routine clinical use [ 49 ].…”

“…The role of HCMV as a tumor promoting virus may depend on the viral strain carried by individual patients. Of high concern, certain clinical strains isolated from patients with breast cancer are able to induce oncogenic and stemness signatures in vitro [ 55 , 56 , 57 ]. In our study, HCMV positivity did not correlate statistically with other factors such as subtypes, grading, sex or age.…”

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis

“…Lipids likely serve as energy stores that help PGCCs endure stress. 157 The increased lipid droplets may serve as energy storage reservoirs that enable cancer TA B L E 2 Main similarities and differences between dormant PGCCs and cancer cells.…”

“…Characteristics of stem cells, such as self-renewal and differentiation ability 18,157 Expression of the embryonic stem cell markers OCT4, NANOG, SOX2 and SSEA1 138 Can differentiate into adipose, cartilage and bone 18…”

Cytomegalovirus at the crossroads of immunosenescence and oncogenesis

“…HCMV-DB and BL, isolated high-risk clinical strains, displayed oncogenic potential in human mammary epithelial cells (HMECs) and replicated in epithelial cells with the interchange of lytic and latent viral cycles promoting the appearance of CMV-transformed HMECs (CTH cells) [60][61][62]. Two additional high-risk HCMV strains, namely biopsy 544 (B544) and B693, recently isolated from enhancer of zeste homolog 2 (EZH2) High Myc High triple-negative breast cancer (TNBC) biopsies revealed oncogenic and stemness potential [63,64]. EZH2 was identified as a downstream target for HCMV-induced Myc upregulation upon HMECs infection with high-risk HCMV strains [64].…”