Vascular endothelial growth factor encoded by Parapoxviruses can regulate metabolism and survival of triple negative breast cancer cells

Abstract

Dysbiotic microbiomes are linked to many pathological outcomes including different metabolic disorders like diabetes, atherosclerosis and even cancer. Breast cancer is the second leading cause of cancer associated death in women, and triple negative breast cancer (TNBC) is the most aggressive type with major challenges for intervention. Previous reports suggested that Parapoxvirus signatures are one of the predominant dysbiotic viral signatures in TNBC. These viruses encode several genes that are homologs of human genes. In this study, we show that the VEGF homolog encoded by Parapoxviruses, can induce cell proliferation, and alter metabolism of breast cancer and normal breast cells, through alteration of MAPK-ERK and PI3K-AKT signaling. In addition, the activity of the transcription factor FoxO1 was altered by viral-encoded VEGF through activation of the PI3K-AKT pathway, leading to reprogramming of cellular metabolic gene expression. Therefore, this study provides new insights into the function of viral-encoded VEGFs, which promoted the growth of the breast cancer cells and imparted proliferative phenotype with altered metabolism in normal breast cells.

The involvement of oncobiosis and bacterial metabolite signaling in metastasis formation in breast cancer

“…However, no differences in the microbiome of the nipple [ 57 , 69 ] and the oral microbiome [ 54 ] between healthy individuals and breast cancer patients have been detected. Besides bacteria, viruses (parapoxviruses [ 91 ], human papillomavirus [ 92 ], Herpesviridae, Retroviridae, Parapoxviridae, Polyomaviridae, Papillomaviridae [ 64 ]), fungi, and parasites were identified in breast cancer tissue [ 64 , 65 , 70 ], although these signatures are not ubiquitous in all individuals. Of note, microbiome signatures in the oncobiome correlate with survival in breast cancer, which underlines the importance of oncobiotic transformation in regulating breast cancer behavior [ 70 ].…”

“…In a fraction of breast cancer cases, intracellular and perinuclear bacteria were identified [ 67 ]. Furthermore, fungi, parasites, and viruses [ 64 , 70 , 91 , 92 ] were detected in tumor tissue. Racial differences were identified in the breast tissue and tumor microbiome [ 59 , 63 ].…”

“…Further underlining these observations, bacterial peptidoglycan rendered breast cancer cells more invasive through activation of TLR2 receptors [ 261 ]. High intratumoral (antibacterial) inflammation can be boosted or sustained by viral infection [ 64 , 91 , 92 ]. In fact, human papillomavirus infection induces Stat3-activation and IL-17 expression in breast cancer patients [ 92 ].…”

Viruses exploit growth factor mechanisms to achieve augmented pathogenicity and promote tumorigenesis

“…In the context of cancer, the breast tumour microenvironment exhibits an abundance of parapoxvirus genomic sequences, which have the potential to impact the metabolism and proliferation of cancer cells. Breast cancer is a malignancy characterized by significant dysregulation of GFs (Bose et al 2020 ).…”

“…Parapoxviruses, abundant in the triple negative breast tumour microenvironment, encode VEGF homologues and modulate the MAPK, ERK and PI3K-AKT pathways. Consequently, these alterations affect cell proliferation and metabolism of both normal and malignant breast cells (Bose et al 2020 ). A VEGF homologue encoded by Orf virus, a member of the parapoxvirus, exhibits robust expression during the initial stages of infection, leading to dermal vascular endothelial proliferation and dilatation (Lyttle et al 1994 ).…”