Obesity-associated inflammation in white adipose tissue (WAT) drives insulin resistance and type 2 diabetes. While UCP1-mediated thermogenesis is a therapeutic target, most browning agents lack anti-inflammatory activity. We aimed to identify small molecules that induce browning and suppress inflammation in human adipocytes. Human cohorts and cell line models were analyzed for inflammatory markers. We generated an in-house multicomponent reaction (MCR)-based chemical library and developed a proprietary high-throughput screening platform to identify UCP1 activators in human adipocytes. Lead compound CDC1011 was evaluated for effects on thermogenesis, mitochondrial respiration, glucose uptake, glycolysis, lipolysis, NF-κB signaling, cytokine secretion, and monocyte chemotaxis. Mechanistic studies assessed cyclic-nucleotide signaling, phosphodiesterase (PDE) inhibition, histone deacetylase (HDAC) modulation, and docking-based predictions. CDC1011 induced UCP1 expression and mitochondrial respiration, enhanced glucose uptake and lipolysis, and suppressed NF-κB activation, cytokine secretion, and monocyte recruitment. Mechanistically, CDC1011 elevated cAMP/PKA and cGMP signaling via PDE inhibition and attenuated HDAC activity, reprogramming adipocytes toward a thermogenic, anti-inflammatory phenotype. CDC1011 is a first-in-class small molecule with dual thermogenic and anti-inflammatory actions in human adipocytes, offering a promising pharmacological strategy for obesity-related metabolic disorders.

Qatar's cancer care strategy is shaped by the National Cancer Strategy (2011) and subsequent frameworks 2017-22, leading to the Qatar Cancer Plan 2023-2026. These initiatives emphasise prevention, early detection, and evidence-based management to reduce the effects of cancer on patients and the health-care system. Investments in advanced medical infrastructure, cutting-edge technology, and specialised professionals have considerably strengthened cancer care. However, challenges remain, including late-stage diagnoses and gaps in public awareness, which underscores the need for enhanced education and global collaboration. Precision medicine, public health initiatives, and research-driven policies position Qatar as a regional leader in oncology. By leveraging its robust health-care and research ecosystem, Qatar aims to advance cancer prevention, diagnosis, and treatment. Aligned with WHO Eastern Mediterranean region goals, the country strives to establish a model of excellence in oncological services.

Admixture mapping has been useful in identifying genetic variations linked to phenotypes, adaptation and diseases. Copy number variations (CNVs) represents genomic structural variants spanning large regions of chromosomes reaching several megabases. In this investigation, the “Canary” algorithm was applied to 102 Tunisian samples and 991 individuals from eleven HapMap III populations to genotype 1279 copy number polymorphisms (CNPs). In this present work, we investigate the Tunisian population structure using the CNP makers previously identified among Tunisian. The study revealed that Sub-Saharan African populations exhibited the highest diversity with the highest proportions of allelic CNPs. Among all the African populations, Tunisia showed the least diversity. Individual ancestry proportions computed using STRUCTURE analysis revealed a major European component among Tunisians with lesser contribution from Sub-Saharan Africa and Asia. Population structure analysis indicated the genetic proximity with Europeans and noticeable distance from the Sub-Saharan African and East Asian clusters. Seven genes harbouring Tunisian high-frequent CNPs were identified known to be associated with 9 Mendelian diseases and/or phenotypes. Functional annotation of genes under selection highlighted a noteworthy enrichment of biological processes to receptor pathway and activity as well as glutathione metabolism. Additionally, pathways of potential concern for health such as drug metabolism, infectious diseases and cancers exhibited significant enrichment. The distinctive genetic makeup of the Tunisians might have been influenced by various factors including natural selection and genetic drift, resulting in the development of distinct genetic variations playing roles in specific biological processes. Our research provides a justification for focusing on the exclusive genome organization of this population and uncovers previously overlooked elements of the genome.

Background and Aims Porto-sinusoidal vascular disorder (PSVD) is a group of liver vascular diseases featuring lesions encompassing the portal venules and sinusoids unaccompanied by cirrhosis, irrespective of the presence/absence of portal hypertension. It can occur secondary to coagulation disorders or insult by toxic agents. However, the cause of PSVD remains unknown in most cases. Hereditary cases of PSVD are exceptionally rare, but they are of particular interest and may unveil genetic alterations and molecular mechanisms associated with the disease. Approach and Results We performed genome sequencing of four patients and two healthy individuals of a large multigenerational Lebanese family with PSVD and identified a heterozygous deleterious variant (c.547C>T, p.R183W) of FCH and double SH3 domains 1 (FCHSD1), an uncharacterized gene, in patients. This variant segregated with the disease, and its pattern of inheritance was suggestive of autosomal dominant with variable expressivity. RNA structural modelling of human FCHSD1 suggests that the C-to-T substitution at position 547, corresponding to FCHSD1(R183W), may increase both messenger RNA (mRNA) and protein stability and its interaction with MTOR-associated protein, LST8 homolog, a key protein of the mechanistic target of rapamycin (mTOR pathway). These predictions were substantiated by biochemical analyses, which showed that FCHSD1(R183W) induced high FCHSD1 mRNA stability, overexpression of FCHSD1 protein, and an increase in mTORC1 activation. This human FCHSD1 variant was introduced into mice through CRISPR/Cas9 genome editing. Nine out of the 15 mice carrying the human FCHSD1(R183W) variant mimicked the phenotype of human PSVD, including splenomegaly and enlarged portal vein. Conclusions Aberrant FCHSD1 structure and function leads to mTOR pathway overactivation and may cause PSVD.

PDF file - 655K, Supplementary Figure 1. TNRC9 promoted cell proliferation in MDA-MB-231 breast cancer cells. Supplementary Figure 2. shRNA-mediated knockdown of TNRC9. Supplementary Figure 3. H&E staining of tumors (10Magnification) from xenograft nude mice subcutaneously injected with control ZR-75-1cells (upper row I V) were compared with those injected with TNRC9-depeltion ZR-75-1 cells (lower row VI VIII, no palpable tumor in two mice). - represents 400μm. Supplementary Figure 4. Knocking-down TNRC9 sensitizes cancer cells to apoptosis signal. Supplementary Figure 5. BRCA1 and TNRC9 expression in TNRC9 abrogated and control cells. Supplementary Figure 6. The expression profile of TNRC9 knockdown MCF-7 cells. Supplementary Figure 7. In silico analysis of TNRC9 and BRCA1 gene expression among ovarian cancer patients. Supplementary Figure 8. The effects of TNRC9 on luciferase activity driven by BRCA1 promoter. Supplementary Table 1 The list of transcripts significantly altered in TNRC9 knockdown MCF-7 cells comparing to control MCF-7 cells

Eighty one percent of adolescents aged 11–17 years are inadequately physically active worldwide. Physical activity (PA) recommendations for high school children have not been studied previously in schools in the Qatar region. The objectives of the study were: (i) to assess the level of compliance of the recommended PA and to assess if there are any gender differences; and (ii) to analyze the recommended step count compliance during school and non-school days. An observational cross-sectional study was conducted. Twenty-nine children (12 boys and 17 girls) aged 13–17 years (15.24 ± 1.46) took part in this study. Participants wore Fitbit Charge 5 wrist bands for three weeks to collect various digital biomarkers including moderate-to-vigorous physical activity (MVPA) and step counts (tracking during out-of-school time and school time). Based on this study, high school children in the two Qatar region schools did not meet the MVPA and steps/day recommendation by the established agencies: 38% of the total study group met the recommended 60 min/day of activity (50% boys, 29% girls). Gender differences were also observed in PA levels and steps per day: for non-school days, 17% met the recommended 10,000 steps/day (25% boys, 12% girls). There was a pattern of greater PA performance and steps during the weekdays as opposed to the weekend, but these values showed no robust evidence in favor of H1 or statistical significance for step counts. However, the evidence was robust in favor of H1 (difference between weekend and weekday) due to a statistically significant difference for meeting the 60 min/day activity. While further studies are required to establish if this is a general trend in Qatari schools, this pilot study does highlight the need to design more effective programs and messaging strategies to improve PA levels in the high school population.

(1) Background: Immunosuppression is a key barrier to effective anti-cancer therapies, particularly in triple-negative breast cancer (TNBC), an aggressive and difficult to treat form of breast cancer. We investigated here whether the combination of doxorubicin, a standard chemotherapy in TNBC with glyceryltrinitrate (GTN), a nitric oxide (NO) donor, could overcome chemotherapy resistance and highlight the mechanisms involved in a mouse model of TNBC. (2) Methods: Balb/C-bearing subcutaneous 4T1 (TNBC) tumors were treated with doxorubicin (8 mg/Kg) and GTN (5 mg/kg) and monitored for tumor growth and tumor-infiltrating immune cells. The effect of treatments on MDSCs reprogramming was investigated ex vivo and in vitro. (3) Results: GTN improved the anti-tumor efficacy of doxorubicin in TNBC tumors. This combination increases the intra-tumor recruitment and activation of CD8+ lymphocytes and dampens the immunosuppressive function of PMN-MDSCs PD-L1low. Mechanistically, in PMN-MDSC, the doxorubicin/GTN combination reduced STAT5 phosphorylation, while GTN +/− doxorubicin induced a ROS-dependent cleavage of STAT5 associated with a decrease in FATP2. (4) Conclusion: We have identified a new combination enhancing the immune-mediated anticancer therapy in a TNBC mouse model through the reprograming of PMN-MDSCs towards a less immunosuppressive phenotype. These findings prompt the testing of GTN combined with chemotherapies as an adjuvant in TNBC patients experiencing treatment failure.

Background Disparities in the genetic risk of cancer among various ancestry groups and populations remain poorly defined. This challenge is even more acute for Middle Eastern populations, where the paucity of genomic data could affect the clinical potential of cancer genetic risk profiling. We used data from the phase 1 cohort of the Qatar Genome Programme to investigate genetic variation in cancer-susceptibility genes in the Qatari population. Methods The Qatar Genome Programme generated high-coverage genome sequencing on DNA samples collected from 6142 native Qataris, stratified into six distinct ancestry groups: general Arab, Persian, Arabian Peninsula, Admixture Arab, African, and South Asian. In this population-based, cohort study, we evaluated the performance of polygenic risk scores for the most common cancers in Qatar (breast, prostate, and colorectal cancers). Polygenic risk scores were trained in The Cancer Genome Atlas (TCGA) dataset, and their distributions were subsequently applied to the six different genetic ancestry groups of the Qatari population. Rare deleterious variants within 1218 cancer susceptibility genes were analysed, and their clinical pathogenicity was assessed by ClinVar and the CharGer computational tools. Findings The cohort included in this study was recruited by the Qatar Biobank between Dec 11, 2012, and June 9, 2016. The initial dataset comprised 6218 cohort participants, and whole genome sequencing quality control filtering led to a final dataset of 6142 samples. Polygenic risk score analyses of the most common cancers in Qatar showed significant differences between the six ancestry groups (p<0001). Qataris with Arabian Peninsula ancestry showed the lowest polygenic risk score mean for colorectal cancer (-0.41), and those of African ancestry showed the highest average for prostate cancer (0.85). Cancer-gene rare variant analysis identified 76 Qataris (1.2% of 6142 individuals in the Qatar Genome Programme cohort) carrying ClinVar pathogenic or likely pathogenic variants in clinically actionable cancer genes. Variant analysis using CharGer identified 195 individuals carriers (3.17% of the cohort). Breast cancer pathogenic variants were over-represented in Qataris of Persian origin (22 [56.4%] of 39 BRCA1/BRCA2 variant carriers) and completely absent in those of Arabian Peninsula origin. Interpretation We observed a high degree of heterogeneity for cancer predisposition genes and polygenic risk scores across ancestries in this population from Qatar. Stratification systems could be considered for the implementation of national cancer preventive medicine programmes. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Migration and invasion inhibitory protein (MIIP) has been identified as a tumor suppressor in various cancer types. Although MIIP is reported to exert tumor suppressive functions by repressing proliferation and metastasis of cancer cells, the detailed mechanism is poorly understood. In the present study, we found MIIP is a favorable indicator of prognosis in triple-negative breast cancer. MIIP could inhibit tumor angiogenesis, proliferation, and metastasis of triple-negative breast cancer cells in vivo and in vitro. Mechanistically, MIIP directly interacted with ITGB3 and suppressed its downstream signaling. As a result, β-catenin was reduced due to elevated ubiquitin-mediated degradation, leading to downregulated VEGFA production and epithelial mesenchymal transition. More importantly, we found RGD motif is essential for MIIP binding with ITGB3 and executing efficient tumor-suppressing effect. Our findings unravel a novel mechanism by which MIIP suppresses tumorigenesis in triple-negative breast cancer, and MIIP is thus a promising molecular biomarker or therapeutic target for the disease.

Immunotherapy has allowed major advances in oncology in the past years, in particular with the development of immune checkpoint inhibitors, but the clinical benefits are still limited, particularly in colorectal cancer (CRC). Our scientific approach is based on the search for innovative immunotherapy with a final goal that aims to induce an effective antitumor immune response in CRC. Here, we focused on a multikinase inhibitor, H89. We carried out in vivo experiments based on syngeneic mouse models of colon cancer in BALB/c mice and chemically colon tumorigenesis. Flow cytometry, RNAseq, RT-qPCR, antibody-specific immune cell depletion, and Western blot were used to identify the immune cell type involved in the preventive and antitumor activity of H89. We demonstrated that H89 delays colon oncogenesis and prevents tumor growth. This latter effect seems to involve NK cells. H89 also inhibits colon tumor growth in a T-cell-dependent manner. Analysis of the immune landscape in the tumor microenvironment showed an increase of CD4 + Th1 cells and CD8 + cytotoxic T cells but a decrease of CD4 + T reg cell infiltration. Mechanistically, we showed that H89 could promote naïve CD4 + T-cell differentiation into Th1, a decrease in T reg differentiation, and an increase in CD8 + T-cell activation and cytotoxicity ex vivo . Furthermore, H89 induced overexpression of genes involved in antitumor immune response, such as IL-15RA, which depletion counteracts the antitumor effect of H89. We also found that H89 regulated Akt/PP2A pathway axis, involved in TCR and IL-15 signaling transduction. Our findings identify the H89 as a potential strategy for immune system activation leading to the prevention and treatment of CRC.

The development of prophylactic and therapeutic agents for coronavirus disease 2019 (COVID-19) is a current global health priority. Here, we investigated the presence of cross-neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in dromedary camels that were Middle East respiratory syndrome coronavirus (MERS-CoV) seropositive but MERS-CoV free. The tested 229 dromedaries had anti–MERS-CoV camel antibodies with variable cross-reactivity patterns against SARS-CoV-2 proteins, including the S trimer and M, N, and E proteins. Using SARS-CoV-2 competitive immunofluorescence immunoassays and pseudovirus neutralization assays, we found medium-to-high titers of cross-neutralizing antibodies against SARS-CoV-2 in these animals. Through linear B cell epitope mapping using phage immunoprecipitation sequencing and a SARS-CoV-2 peptide/proteome microarray, we identified a large repertoire of Betacoronavirus cross-reactive antibody specificities in these dromedaries and demonstrated that the SARS-CoV-2–specific VHH antibody repertoire is qualitatively diverse. This analysis revealed not only several SARS-CoV-2 epitopes that are highly immunogenic in humans, including a neutralizing epitope, but also epitopes exclusively targeted by camel antibodies. The identified SARS-CoV-2 cross-neutralizing camel antibodies are not proposed as a potential treatment for COVID-19. Rather, their presence in nonimmunized camels supports the development of SARS-CoV-2 hyperimmune camels, which could be a prominent source of therapeutic agents for the prevention and treatment of COVID-19.

Copy number variation (CNV) is considered as the most frequent type of structural variation in the human genome. Some CNVs can act on human phenotype diversity, encompassing rare Mendelian diseases and genomic disorders. The North African populations remain underrepresented in public genetic databases in terms of single-nucleotide variants as well as for larger genomic mutations. In this study, we present the first CNV map for a North African population using the Affymetrix Genome-Wide SNP (single-nucleotide polymorphism) array 6.0 array genotyping intensity data to call CNVs in 102 Tunisian healthy individuals. Two softwares, PennCNV and Birdsuite, were used to call CNVs in order to provide reliable data. Subsequent bioinformatic analyses were performed to explore their features and patterns. The CNV map of the Tunisian population includes 1083 CNVs spanning 61.443 Mb of the genome. The CNV length ranged from 1.017 kb to 2.074 Mb with an average of 56.734 kb. Deletions represent 57.43% of the identified CNVs, while duplications and the mixed loci are less represented. One hundred and three genes disrupted by CNVs are reported to cause 155 Mendelian diseases/phenotypes. Drug response genes were also reported to be affected by CNVs. Data on genes overlapped by deletions and duplications segments and the sequence properties in and around them also provided insights into the functional and health impacts of CNVs. These findings represent valuable clues to genetic diversity and personalized medicine in the Tunisian population as well as in the ethnically similar populations from North Africa.

Abstract Background Although autophagy plays a dual role in suppressing or promoting certain cancers, the nature of its involvement in breast cancers remains unclear. Here, we investigated the function of STXBP6, a protein regulating the autophagy‐associated SNARE complex, in triple negative breast cancer (TNBC). Results We report that STXBP6 is profoundly downregulated in TNBC specimens in association with reduced overall patient survival. Notably, we found that STXBP6 promoter was specifically hyper‐methylated in TNBC specimens. Ectopic expression of STXBP6 inhibited TNBC cell proliferation in cellular and mouse models. Mass spectrometric analysis revealed physical interactions of STXBP6 with a number of autophagy‐related proteins including SNX27, a molecule involved in endocytosis of plasma membrane receptors and protein trafficking. Overexpression of STXBP6 elicited autophagy through inhibition of mTORC1 signaling. Reciprocally, induction of autophagy rescued STXBP6 expression by inhibiting EZH2 and altering STXBP6 methylation. The mutual regulation between STXBP6 and autophagy was replicated in luminal breast cancer cells only when estrogen receptor (ER) activation was abrogated. Ectopic expression of STXBP6 significantly reduced TNBC cells’ migratory ability in vitro and tumor metastasis in vivo. Conclusions Our results unveil a role of STXBP6 in TNBC that highlights a new paradigm in autophagy regulation. Our results significantly enhance the understanding of the mechanisms of TNBC aggressiveness, which might help in designing novel therapies targeting TNBC.

Aberrant metabolism is the root cause of several serious health issues, creating a huge burden to health and leading to diminished life expectancy. A dysregulated metabolism induces the secretion of several molecules which in turn trigger the inflammatory pathway. Inflammation is the natural reaction of the immune system to a variety of stimuli, such as pathogens, damaged cells, and harmful substances. Metabolically triggered inflammation, also called metaflammation or low-grade chronic inflammation, is the consequence of a synergic interaction between the host and the exposome—a combination of environmental drivers, including diet, lifestyle, pollutants and other factors throughout the life span of an individual. Various levels of chronic inflammation are associated with several lifestyle-related diseases such as diabetes, obesity, metabolic associated fatty liver disease (MAFLD), cancers, cardiovascular disorders (CVDs), autoimmune diseases, and chronic lung diseases. Chronic diseases are a growing concern worldwide, placing a heavy burden on individuals, families, governments, and health-care systems. New strategies are needed to empower communities worldwide to prevent and treat these diseases. Precision medicine provides a model for the next generation of lifestyle modification. This will capitalize on the dynamic interaction between an individual’s biology, lifestyle, behavior, and environment. The aim of precision medicine is to design and improve diagnosis, therapeutics and prognostication through the use of large complex datasets that incorporate individual gene, function, and environmental variations. The implementation of high-performance computing (HPC) and artificial intelligence (AI) can predict risks with greater accuracy based on available multidimensional clinical and biological datasets. AI-powered precision medicine provides clinicians with an opportunity to specifically tailor early interventions to each individual. In this article, we discuss the strengths and limitations of existing and evolving recent, data-driven technologies, such as AI, in preventing, treating and reversing lifestyle-related diseases.

Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease. It is transmitted as autosomal recessive trait with mutations in MEditerranean FeVer (MEFV)gene. Despite a typical clinical expression, many patients have either a single or no mutation inMEFV. The current work is aimed to revisit the genetic landscape of FMF disease using high-coverage whole genome sequencing. In atypical patients (carrying a single or no mutation inMEFV), we revealed many rare variants in genes associated with auto-inflammatory disorders, and more interestingly, we discovered a novel variant ( a 2.1-Kb deletion) in exon 11 ofIL1RL1gene, present only in patients. To validate and screen this patient-specific variant, a tandem of allele-specific PCR and quantitative real-time PCR was performed in 184 FMF patients and 218 healthy controls and we demonstrated that the novel deletion was absent in controls and was present in more than 19% of patients. This study sheds more light on the mutational landscape of FMF. Our discovery of a disease-specific variant inIL1RL1gene may constitute a novel genetic marker for FMF. This finding suggesting a potential role of the IL33/ST2 signalling in the disease pathogenicity highlights a new paradigm in FMF pathophysiology.

Recessive mutations in the TMTC3 gene have been reported in thirteen patients to date exhibiting development delay, intellectual disability (ID), seizures, and muscular hypotonia, accompanied occasionally by neuronal migration defects expressed as either cobblestone lissencephaly or periventricular hypertopia. Here, we report a new case of a TMTC3-related syndrome in a Lebanese family with two affected siblings showing severe psychomotor retardation, intellectual disability, microcephaly, absence of speech, muscular hypotonia, and seizures. Whole exome sequencing revealed a homozygous pathogenic variant c.211 C > T (p.R71C) in the TMTC3 gene in both siblings. A review of the literature on TMTC3-related syndrome and its causal mutations is provided.

Abstract Background:Triple-negative breast cancer (TNBC) has a higher rate of early relapse and mortality compared to other types of breast cancer (BC). CCL5 and its signaling pathway have been linked to TNBC. Methods:We characterized variants in CCL5and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21 and HS6ST3) among 1,082 unrelated Arab subjects, including 196 TNBC, accessed their association with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 expression with CCL5genotypes. Results: CCND1 rs614367-TTgenotype was highly associated with the TNBC risk (OR = 5.14; P = 0.004) and the rs614367-Tallele was associated with decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5variants (rs2107538and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21rs1294255-G allele was associated with a decreased OVS. High expression of CCL5in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. Conclusion:Genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggression. Citation Format: Salha Bujassoum Al-Bader, Jingxuan Shan, David Bedognetti, Lotfi Chouchane. Genetic variants of CCL5 signaling pathway genes in susceptibility and prognosis of triple negative breast cancers in Arab population [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-09-10.

Triple-negative breast cancer (TNBC) accounts for ~15-20% of breast cancer (BC) and has a higher rate of early relapse and mortality compared to other subtypes. The Chemokine (C-C motif) ligand 5 (CCL5) and its signaling pathway have been linked to TNBC. We aimed to investigate the susceptibility and prognostic implications of genetic variation in CCL5 signaling genes in TNBC in the present study. We characterized variants in CCL5 and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21, and HS6ST3) among 1,082 unrelated Tunisian subjects (544 BC patients, including 196 TNBC, and 538 healthy controls), assessed the association of the variants with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 mRNA and serum levels with CCL5 genotypes. We found a highly significant association between the CCND1 rs614367-TT genotype (OR = 5.14; P = 0.004) and TNBC risk, and identified a significant association between the rs614367-T allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21 rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5 variants (rs2107538 and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21 rs1294255-G allele was associated with a decreased OVS. High expression of CCL5 in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. In conclusion, genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggressiveness.

Abstract Triple negative breast cancer (TNBC) is a subtype of breast cancer (BC) that accounts for approximately 15–20% of all BCs. Additionally, TNBC presents with a poor prognosis mainly due to the lack of effective therapeutic options. For this reason, numerous studies have focused to find the potential molecular targets. Syntaxin binding protein 6, encoded by STXBP6, was initially identified in regulating the formation of the SNARE complex and cytogenesis. It has been reported to be associated with many diseases, such as diabetes, autism and systemic lupus erythematosus. However, there are no studies revealing its biological role and its epigenetic regulation in TNBC. Thus, herein we aim to demonstrate antitumor implications of STXBP6 in TNBC. In this study first, we explored the clinical significance of STXBP6 in cancer. Pan-cancer profiling using TCGA data sets identified aberrant expression of STXBP6 in different cancer types. Importantly, we identified significant down regulation of STXBP6 in TNBC samples. Moreover, significantly improved survival rates were observed in patients when STXBP6 expression levels high. The concurrent analysis between gene expression and methylation of STXBP6 highlighted a clear negative correlation. When the luminal subtype and TNBC subtype of BC cells were treated with demethylating agent 5-aza-2’-deoxycytidine, we observed an increase in the expression of STXBP6 in TNBC cells only which further support the regulatory role of DNA methylation in the control of STXBP6 expression in TNBC. Next, we elucidated the function of STXBP6 in TNBC cells. Overexpression of STXBP6 in TNBC cells significantly decreased cell proliferation, colony formation and increased apoptosis. In summary, these findings highlight the suppression effect of STXBP6 on TNBC progression and could be a novel prognostic and therapeutic target for TNBC in the future. Key Words: STXBP6, Gene Expression, Methylation, Tumor Suppressor, Triple Negative Breast Cancer. Citation Format: Govinda Lenka, Jingxuan Shan, Sirin Abuaqel, Lotfi Chouchane. The tumor suppressor role of STXBP6 in triple negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C120. doi:10.1158/1535-7163.TARG-19-C120