Epstein-Barr Virus Selects for Stem Cell Lineages in Breast Cancer and Normal Tissues

Abstract

Epstein-Barr virus (EBV) causes persistent damage to breast cancer genomes, so viral particles need not be continually present to cause malignancy. Because basal type stem cells are present in breast cancer but missing in normal breast, the hypothesis was tested that EBV creates or selects for breast cancer stem cells. Bioinformatic comparisons identified methylation of cis-regulators of gene expression in breast cancer chromosomes that closely matched EBV-associated cancers. On certain chromosomes, most of these methylated regulators governed stem cell related differentiation pathways. The shared methylation sites were found in breast cancers typical of the basal layer, where breast stem cells are thought to originate. A few of the same shared breast cancer methylation marks were detected in non-malignant keratinocytes with a cured EBV infection, suggesting EBV epigenetic changes are difficult to reverse. Control experiments with methylation sites on chromosome 17 in (non-EBV) skin cell carcinoma did not correspond to abnormal methylation in breast cancer. Moreover, randomly generated epigenetic sites showed negligible overlap with EBV cancers, so the observed matches are unlikely in non-EBV cancers and unlikely due to chance. Additionally, breast cancer genomes had variable damage to immune responses typical of EBV infection, so immune variation helps explain why not everyone gets EBV cancer. Coupled with other breast cancer safeguards compromised by EBV, epigenetic changes in stem cell related genes that match EBV cancers make the breast more susceptible to cancer triggers.