BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer

Germline mutations in the BRCA1 or BRCA2 genes are associated with an increased risk of breast and ovarian cancer development. Both genes are involved in DNA repair, and tumors harboring genetic defects in them are thought to be more sensitive to DNA-damaging agents used in chemotherapy. However, as only a minority of breast and ovarian cancer patients carry BRCA1 or BRCA2 mutations, few patients are likely to benefit from these pharmacogenetic biomarkers. Herein, we show that, in cancer cell lines and xenografted tumors, BRCA1 CpG island promoter hypermethylation-associated silencing also predicts enhanced sensitivity to platinum-derived drugs to the same extent as BRCA1 mutations. Most importantly, BRCA1 hypermethylation proves to be a predictor of longer time to relapse and improved overall survival in ovarian cancer patients undergoing chemotherapy with cisplatin.     

BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer

Germline mutations in the BRCA1 or BRCA2 genes are associated with an increased risk of breast and ovarian cancer development. Both genes are involved in DNA repair, and tumors harboring genetic defects in them are thought to be more sensitive to DNA-damaging agents used in chemotherapy. However, as only a minority of breast and ovarian cancer patients carry BRCA1 or BRCA2 mutations, few patients are likely to benefit from these pharmacogenetic biomarkers. Herein, we show that, in cancer cell lines and xenografted tumors, BRCA1 CpG island promoter hypermethylation-associated silencing also predicts enhanced sensitivity to platinum-derived drugs to the same extent as BRCA1 mutations. Most importantly, BRCA1 hypermethylation proves to be a predictor of longer time to relapse and improved overall survival in ovarian cancer patients undergoing chemotherapy with cisplatin.     

Association between SNP rs527616 in lncRNA AQP4-AS1 and susceptibility to breast cancer in a southern Brazilian population

Breast cancer (BC) is the leading cause of death by this disease in women worldwide. Among the factors involved in tumorigenesis, long non-coding RNAs (lncRNAs) and their differential expression have been associated. Differences in gene expression may be triggered by variations in DNA sequence, including single nucleotide polymorphisms (SNPs). In the present study, we analyzed the rs527616 (C>G), located in the lncRNA AQP4-AS1, using PCR-SSP in 306 BC patients and 312 controls, from a Brazilian population. In the BC group, the frequency found for CG heterozygotes was above the expected and the overdominant model is the best one to explain our results (OR: 1.70, IC 95%: 1.23-2.34, P<0.001). Furthermore, the SNP were associated with age at BC diagnosis and the risk genotype more frequent in the older age group. According to TCGA data, AQP4-AS1 is down-regulated in BC tissue, and the overexpression is associated with better prognoses, including Luminal A, HER2-, stage 1 of disease and smaller tumor. In conclusion, the CG genotype is associated with increased susceptibility in the southern Brazilian population. This SNP is mapped in the lncRNA AQP4-AS1, showing differential expression in BC samples. Based on these results, we emphasize the potential of the role of AQP4-AS1 in cancer.     

MiR-526b targets lncRNA SLC16A1-AS1 to suppress cell proliferation in triple-negative breast cancer

The present study investigated the potential interaction between miR-526b and lncRNA SLC16A1-AS1 in triple-negative breast cancer (TNBC). Expression of miR-526b and SLC16A1-AS1 in TNBC tumor tissues and paired nontumor tissues from 60 TNBC patients was detected by real-time polymerase chain reaction (RT-qPCR). The interaction between miR-526b and SLC16A1-AS1 was evaluated with overexpression experiments, followed by RT-qPCR. The proliferation and migration of cells were detected with cell counting kit-8 assay and Transwell assay, respectively. Apoptosis of cells was assessed by cell apoptosis assay. The expression of apoptosis-related proteins was quantified by Western blot analysis. MiR-526b was predicted to bind with SLC16A1-AS1. Overexpression of miR-526b in TNBC cells decreased the expression levels of SLC16A1-AS1, while overexpression of SLC16A1-AS1 did not affect the expression of miR-526b. In TNBC tissues, miR-526b was downregulated in TNBC tissues, while SLC16A1-AS1 was upregulated in TNBC tissues compared to that in nontumor tissues. The expression of SLC16A1-AS1 and miR-526b were inversely correlated. In vitro experiments showed that overexpression of SLC16A1-AS1 promoted cell proliferation and invasion but suppressed cell apoptosis. MiR-526b played an opposite role and suppressed the function of SLC16A1-AS1. MiR-526b is downregulated in TNBC and it targets SLC16A1-AS1 to regulate proliferation, apoptosis, and invasion of TNBC cells.     

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

Non-small cell lung cancer (NSCLC) still constitutes the most common cancer-related cause of death worldwide. All efforts to introduce suitable treatment options using chemotherapeutics or targeted therapies have, up to this point, failed to exhibit a substantial effect on the 5-year-survival rate. The involvement of epigenetic alterations in the evolution of different cancers has led to the development of epigenetics-based therapies, mainly targeting DNA methyltransferases (DNMTs) and histone-modifying enzymes. So far, their greatest success stories have been registered in hematologic neoplasias. As the effects of epigenetic single agent treatment of solid tumors have been limited, the investigative focus now lies on combination therapies of epigenetically active agents with conventional chemotherapy, immunotherapy, or kinase inhibitors. This review includes a short overview of the most important preclinical approaches as well as an extensive discussion of clinical trials using epigenetic combination therapies in NSCLC, including ongoing trials. Thus, we are providing an overview of what lies ahead in the field of epigenetic combinatory therapies of NSCLC in the coming years.     

Co-transplantation of human hematopoietic stem cells and human breast cancer cells in NSG mice: A novel approach to generate tumor cell specific human antibodies

Humanized tumor mice (HTM) were generated by the co-transplantation of human hematopoietic stem cells and human breast cancer cells overexpressing HER2 into neonatal NOD-scid IL2Rγ^null (NSG) mice. These mice are characterized by the development of a human immune system in combination with human breast cancer growth. Due to concurrent transplantation into newborn mice, transfer of MHC-mismatched tumor cells resulted in solid coexistence and immune cell activation (CD4⁺ T cells, natural killer cells, and myeloid cells), but without evidence for rejection. Histological staining of the spleen of HTM revealed co-localization of human antigen-presenting cells together with human T and B cells allowing MHC-dependent interaction, and thereby the generation of T cell-dependent antibody production. Here, we investigated the capability of these mice to generate human tumor-specific antibodies and correlated immunoglobulin titers with tumor outgrowth. We found detectable IgM and also IgG amounts in the serum of HTM, which apparently controlled tumor development when IgG serum concentrations were above 10 µg/ml. Western blot analyses revealed that the tumor-specific antibodies generated in HTM did not recognize HER2/neu antigens, but different, possibly relevant antigens for breast cancer therapy. In conclusion, HTM offer a novel approach to generate complete human monoclonal antibodies that do not require further genetic manipulation (e. g., humanization) for a potential application in humans. In addition, efficacy and safety of the generated antibodies can be tested in the same mouse model under human-like conditions. This might be of particular interest for cancer subtypes with no currently available antibody therapy.     

The epicenter of chromosomal fragility of Fra14A2, the mouse ortholog of human FRA3B common fragile site,is largely attached to the nuclear matrix in lymphocytes but not in other cell types that do not express such a fragility

Common fragile sites (CFSs) correspond to chromosomal regions susceptible to present breaks, discontinuities or constrictions in metaphase chromosomes from cells subjected to replication stress. They are considered as genomic regions intrinsically difficult to replicate and they are evolutionary conserved at least in mammals. However, the recent discovery that CFSs are cell-type specific indicates that DNA sequence by itself cannot account for CFS instability. Nevertheless, the large gene FHIT that includes FRA3B, the most highly expressed CFS in human lymphocytes, is commonly deleted in a variety of tumors suggesting a tumor suppressor role for its product. Here, we report that the epicenter of fragility of Fra14A2/Fhit, the mouse ortholog of human FRA3B/FHIT that like its human counterpart is the most highly expressed CFS in mouse lymphocytes, is largely attached to the nuclear matrix compartment in naive B lymphocytes but not in primary hepatocytes or cortical neurons that do not express such a CFS. Our results suggest a structural explanation for the difficult-to-replicate nature of such a region and so for its common fragility in lymphocytes, that is independent of the possible tumor suppressor role of the gene harboring such CFS.