Oncoviruses are implicated in around 20% of all human cancers including both solid and non-solid malignancies. Epstein–Barr virus (EBV) and human papillomaviruses (HPVs) are the most common oncoviruses worldwide. Currently, it is well established that onco-proteins of EBV (LMP1, LMP2A, and EBNA1) and high-risk HPVs (E5 and E6/E7) play an important role in the initiation and/or progression of several human carcinomas, including cervical, oral, and breast. More significantly, it has been recently pointed out that viral onco-proteins of EBV and high-risk HPVs can be co-present and consequently cooperate to initiate and/or amplify epithelial–mesenchymal transition (EMT), which is the hallmark of cancer progression and metastasis. This could occur by β-catenin, JAK/STAT/SRC, PI3k/Akt/mTOR, and/or RAS/MEK/ERK signaling pathways, which onco-proteins of EBV and HPVs share. This review presents the most recent advances related to EBV and high-risk HPVs onco-proteins interactions and their roles in the progression of human carcinomas especially oral and breast via the initiation of EMT.

Breast cancer, the most frequent disease amongst women worldwide, accounts for the highest cancerrelated mortality rate. Triple-negative breast cancer (TNBC) subtype encompasses ~15% of all breast cancers and lack estrogen, progesterone, and HER2 receptors. Although risk factors for breast cancer are well-known, factors underpinning breast cancer onset and progression remain unknown. Recent studies suggest the plausible role of oncoviruses including human papillomaviruses (HPVs), Epstein-Barr virus (EBV), and mouse mammary tumor virus (MMTV) in breast cancer pathogenesis. However, the role of these oncoviruses in TNBC is still unclear. In the current study, we explored the status of high-risk HPVs, EBV, and MMTV in a well-defined TNBC cohort from Croatia in comparison to 16 normal/non TNBC samples (controls) using polymerase chain reaction assay. We found high-risk HPVs and EBV present in 37/70 (53%) and 25/70 (36%) of the cases, respectively. The most common HPV types are 52, 45, 31, 58 and 68. We found 16% of the samples positive for co-presence of high-risk HPVs and EBV. Moreover, our data revealed that 5/70 (7%) samples are positive for MMTV. In addition, only 2/70 (3%) samples had copresence of HPVs, EBV, and MMTV without any significant association with the clinicopathological variables. While, 6/16 (37.5%) controls were positive for HPV (p = .4), EBV was absent in all controls (0/ 16, 0%) (p = .01). In addition, we did not find the co-presence of the oncoviruses in the controls (p > .05). Nevertheless, further investigations are essential to understand the underlying mechanisms of multipleoncogenic viruses' interaction in breast carcinogenesis, especially TNBC.

Elaeagnus angustifolia (EA) is used as an alternative medicine in the Middle East to manage numerous human diseases. We recently reported that EA flower extract inhibits cell proliferation and invasion of human oral and HER2-positive breast cancer cells. Nevertheless, the outcome of EA extract on triple-negative breast cancer (TNBC) cells has not been explored yet. We herein investigate the effect of the aqueous EA extract (100 and 200 μl/ml) on two TNBC cell lines (MDA-MB-231 and MDA-MB-436) for 48 h and explore its underlying molecular pathways. Our data revealed that EA extract suppresses cell proliferation by approximately 50% and alters cell-cycle progression of these two cancer cell lines. Additionally, EA extract induces cell apoptosis by 40–50%, accompanied by the upregulation of pro-apoptotic markers (Bax and cleaved caspase-8) and downregulation of the anti-apoptotic marker, Bcl-2. Moreover, EA extract inhibits colony formation compared to their matched control. More significantly, the molecular pathway analysis of EA-treated cells revealed that EA extract enhances p53 expression, while inhibiting the expression of total and phosphorylated Signal Transducer and Activator Of Transcription 3 (STAT3) in both cell lines, suggesting p53 and STAT3 are the main key players behind the biological events provoked by the extract in TNBC cells. Our findings implicate that EA flower extract may possess an important potential as an anticancer drug against TNBC.

Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies.

The objective of this study was to evaluate the role of activated protein C (aPC), known to be a physiological anticoagulant, in ovarian cancer cell activation as well as in loss of clotting of cancer ascitic fluid. The effect of aPC on an ovarian cancer cell line (OVCAR-3) was tested in regards to i) cell migration and adhesion with the use of adhesion and wound healing assays as well as a droplet test; ii) protein phosphorylation, evaluated by cyto-ELISA; iii) cell cycle modification assessed by flow cytometric DNA quantification; and iv) anticoagulant activity evaluated by the prolongation of partial thromboplastin time (aPTT) of normal plasma in the presence or absence of aPC-treated ovarian cancer cells. In addition, the soluble endothelial protein C receptor (sEPCR) was quantified by ELISA in ascitic fluid of patients with ovarian cancer. Our results showed that in the OVCAR-3 aPC-induced cells i) an increase in cell migration was noted, which was inhibited when anti-endothelial protein C receptor (EPCR) was added to the culture medium and which may act via MEK-ERK and Rho-GTPase pathways; ii) an increase in threonine, and to a lesser extent tyrosine phosphorylation; iii) cell cycle activation (G1 to S/G2); and iv) a 2-3-fold prolongation of aPTT of normal plasma. In the peritoneal fluid, the sEPCR concentration was 71±23 ng/ml. In conclusion, free aPC binds to membrane EPCR in ovarian cancer cells and induces cell migration via MEK-ERK and Rho-GTPase pathways. This binding could also explain the loss of clotting of peritoneal fluids.