Background: The adhesion molecule, FAT4, has a tumor suppressor function with a critical role in the epithelial-to-mesenchymal-transition (EMT) and anti-malignant growth in several cancers. No study has investigated yet its role in epithelial ovarian cancer (EOC) progression. In the present study, we examined the role of FAT4 in proliferation and metastasis, and its mechanisms of interaction in these processes. Methods: We have performed cell viability, colony formation, and invasion assays in ovarian cancer cells treated with siRNA to knockdown FAT4 gene expression. The regulatory effects of FAT4 on proteins involved in apoptotic, Wnt, Hippo, and retinoblastoma signaling pathways were evaluated by Western blotting following FAT4 repression. Also, 426 ovarian tumor samples and 88 non-tumor samples from the Gene Expression Profiling Interactive Analysis (GEPIA) database were analyzed for the expression of FAT4. Pearson’s correlation was performed to determine the correlation between FAT4 and the E2F5, cyclin D1, cdk4, and caspase 9 expressions. Results: Lower expression of FAT4 was observed in ovarian cancer cell lines and human samples as compared to non-malignant tissues. This down-regulation seems to enhance cell viability, invasion, and colony formation. Silencing FAT4 resulted in the upregulation of E2F5, vimentin, YAP, β-catenin, cyclin D1, cdk4, and Bcl2, and in the downregulation of GSK-3-β, and caspase 9 when compared to control. Furthermore, regulatory effects of FAT4 on the EMT and aggressive phenotype seem to occur through Hippo, Wnt, and cell cycle pathways. Conclusion: FAT4 downregulation promotes increased growth and invasion through the activation of Hippo and Wnt-β-catenin pathways.

In Oman, breast cancer is most common, representing approximately more than 25% of all cancers in women. Relatively younger populations of patients (25–40 years) present surprisingly with an aggressive phenotype and advanced tumor stages. In this study, we investigated differential gene expressions in Luminal A, Luminal B, triple-negative and Her2+ breast cancer subtypes and compared data to benign tumor samples. We identified a potential candidate gene BRIP1 , showing differential expression in the four breast cancer subtypes examined, suggesting that BRIP1 has the profile of a useful diagnostic marker, suitable for targeted therapeutic intervention. RT-qPCR and Western blotting analysis showed higher BRIP1 expression in luminal samples as compared to triple-negative subtype patient’s samples. We further screened BRIP1 for eventual mutations/SNPs/deletions by sequencing the entire coding region. Four previously identified polymorphisms were detected, one within the 5′-UTR region (c.141-64G > A) and three in the BRCA -binding domain (c.2755T > C, c.2647G > A and c.3411T > C). Kaplan–Meier analysis revealed that patients with overexpression of BRIP1 displayed a poor survival rate ( P < 0.05). BRIP1 has a dual function of an oncogene and a tumor suppressor gene in addition to its role as a potential biomarker to predict survival and prognosis. Data obtained in this study suggest that BRIP1 can plausibly have an oncogenic role in sporadic cancers.

Breast and ovarian cancer are heterogeneous diseases. While breast cancer accounts for 25% of cancers worldwide, ovarian cancer accounts for 3.5% of all cancers and it is considered to be the most lethal type of cancer among women. In Oman, breast cancer accounts for 25% and ovarian cancer for 4.5% of all cancer cases. Various risk factors, including variable biological and clinical traits, are involved in the onset of breast and ovarian cancer. Although highly developed diagnostic and therapeutic methods have paved the way for better management, targeted therapy against specific biomarkers has not yet shown any significant improvement, particularly in triple‑negative breast cancer and epithelial ovarian cancer, which are associated with high mortality rates. Thus, elucidating the mechanisms underlying the pathology of these diseases is expected to improve their prevention, prognosis and management. The aim of the present study was to provide a comprehensive review and updated information on genomics and proteomics alterations associated with cancer pathogenesis, as reported by several research groups worldwide. Furthermore, molecular research in our laboratory, aimed at identifying new pathways involved in the pathogenesis of breast and ovarian cancer using microarray and chromatin immunoprecipitation (ChIP), is discussed. Relevant candidate genes were found to be either up‑ or downregulated in a cohort of breast cancer cases. Similarly, ChIP analysis revealed that relevant candidate genes were regulated by the E2F5 transcription factor in ovarian cancer tissue. An ongoing study aims to validate these genes with a putative role as biological markers that may contribute to the development of targeted therapies for breast and ovarian cancer.

More than two-thirds of epithelial ovarian cancer (EOC) patients are diagnosed at advanced stages due to the lack of sensitive biomarkers. Currently, exosomes are intensively investigated as non-in... Plain language summary Exosomes are nanovesicles released in the extracellular milieu by diverse cell types and serve as carriers of proteins, and nucleic acids, with the potential to modulate the ... Graphical abstract

High-grade epithelial ovarian cancer is a fatal disease in women frequently associated with drug resistance and poor outcomes. We previously demonstrated that a marine-derived compound MalforminA1 (MA1) was cytotoxic for the breast cancer cell line MCF-7. In this study, we aimed to examine the effect of MA1 on human ovarian cancer cells. The potential cytotoxicity of MA1was tested on cisplatin-sensitive (A2780S) and cisplatin-resistant (A2780CP) ovarian cancer cell lines using AlamarBlue assay, Hoechst dye, flow cytometry, Western blot, and RT-qPCR. MA1 had higher cytotoxic activity on A2780S (IC50 = 0.23 µM) and A2780CP (IC50 = 0.34 µM) cell lines when compared to cisplatin (IC50 = 31.4 µM and 76.9 µM, respectively). Flow cytometry analysis confirmed the cytotoxic effect of MA1. The synergistic effect of the two drugs was obvious, since only 13% of A2780S and 7% of A2780CP cells remained alive after 24 h of treatment with both MA1 and cisplatin. Moreover, we examined the expression of bcl2, p53, caspase3/9 genes at RNA and protein levels using RT-qPCR and Western blot, respectively, to figure out the cell death mechanism induced by MA1. A significant down-regulation in bcl2 and p53 genes was observed in treated cells compared to non-treated cells (p < 0.05), suggesting that MA1 may not follow the canonical pathway to induce apoptosis in ovarian cancer cell lines. MalforminA1 showed promising anticancer activity by inducing cytotoxicity in cisplatin-sensitive and cisplatin-resistant cancer cell lines. Interestingly, a synergistic effect was observed when MA1 was combined with cisplatin, leading to it overcoming its resistance to cisplatin.