scholarly journals Multi-omics data integration reveals correlated regulatory features of triple negative breast cancer

2021 ◽  
Author(s):  
Kevin Chappell ◽  
Kanishka Manna ◽  
Charity L. Washam ◽  
Stefan Graw ◽  
Duah Alkam ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Data Integration ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Biological Pathways ◽  
Omics Data ◽  
Insight Into ◽  
Omics Data Integration

Multi-omics data integration of triple negative breast cancer (TNBC) provides insight into biological pathways.

scholarly journals Novel miRNA Targets and Therapies in the Triple-Negative Breast Cancer Microenvironment: An Emerging Hope for a Challenging Disease

2020 ◽  
Vol 21 (23) ◽  
pp. 8905
Author(s):  
Amal Qattan
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epidermal Growth Factor Receptors ◽  
Mirna Regulation ◽  
Novel Mirna ◽  
Epidermal Growth ◽  
Cell Subpopulations ◽  
Insight Into

Treatment of triple-negative breast cancer (TNBC) remains challenging because of the heterogeneity of the disease and lack of single targetable driving mutations. TNBC does not rely on estrogen, progesterone or epidermal growth factor receptors and is associated with aggressive disease progression and poor prognosis. TNBC is also characterized by resistance to chemotherapeutics, and response to immunotherapies is limited despite promising results in a subset of TNBC patients. MicroRNAs (miRNAs) have emerged as significant drivers of tumorigenesis and tumor progression in triple-negative breast cancer (TNBC) and present unique opportunities to target various components of the TNBC microenvironment for improved efficacy against this difficult to treat cancer. Effects of miRNAs on multiple targets may improve response rates in the context of this genetically and biologically heterogeneous disease. In this review, we offer a comprehensive view of miRNA regulation in TNBC, treatment challenges presented by TNBC in the context of the tumor microenvironment and stem cell subpopulations, and current and emerging miRNA-based therapeutic strategies targeting various components of the TNBC microenvironment. In addition, we offer insight into novel targets that have potential for treating TNBC through multiple mechanisms in the tumor microenvironment simultaneously and those that may be synergistic with standard chemotherapies.

scholarly journals Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer

2019 ◽  
Vol 16 (6) ◽  
pp. 1055 ◽  
Author(s):  
Jiande Wu ◽  
Tarun Mamidi ◽  
Lu Zhang ◽  
Chindo Hicks
Keyword(s):  
Breast Cancer ◽  
Somatic Mutation ◽  
Triple Negative Breast Cancer ◽  
Somatic Mutations ◽  
Triple Negative ◽  
Germline Mutations ◽  
Biological Pathways ◽  
Molecular Networks ◽  
Increased Risk ◽  
Mutation Information

Recent advances in high-throughput genotyping and the recent surge of next generation sequencing of the cancer genomes have enabled discovery of germline mutations associated with an increased risk of developing breast cancer and acquired somatic mutations driving the disease. Emerging evidence indicates that germline mutations may interact with somatic mutations to drive carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic alterations in triple-negative breast cancer (TNBC) have not been characterized. The objective of this study was to investigate the possible oncogenic interactions and cooperation between genes containing germline and somatic mutations in TNBC. Our working hypothesis was that genes containing germline mutations associated with an increased risk developing breast cancer also harbor somatic mutations acquired during tumorigenesis, and that these genes are functionally related. We further hypothesized that TNBC originates from a complex interplay among and between genes containing germline and somatic mutations, and that these complex array of interacting genetic factors affect entire molecular networks and biological pathways which in turn drive the disease. We tested this hypothesis by integrating germline mutation information from genome-wide association studies (GWAS) with somatic mutation information on TNBC from The Cancer Genome Atlas (TCGA) using gene expression data from 110 patients with TNBC and 113 controls. We discovered a signature of 237 functionally related genes containing both germline and somatic mutations. We discovered molecular networks and biological pathways enriched for germline and somatic mutations. The top pathways included the hereditary breast cancer and role of BRCA1 in DNA damage response signaling pathways. In conclusion, this is the first large-scale and comprehensive analysis delineating possible oncogenic interactions and cooperation among and between genes containing germline and somatic mutations in TNBC. Genetic and somatic mutations, along with the genes discovered in this study, will require experimental functional validation in different ethnic populations. Functionally validated genetic and somatic variants will have important implications for the development of novel precision prevention strategies and discovery of prognostic markers in TNBC.

Blocking pro-invasive signaling and inflammatory activation in triple-negative breast cancer with nucleic-acid scavengers (NASs).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13096-e13096
Author(s):  
Elias Eteshola ◽  
Karenia Landa ◽  
Eun-Sil Shelley Hwang ◽  
Smita Nair ◽  
Bruce Sullenger
Keyword(s):  
Breast Cancer ◽  
Nucleic Acid ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Chemotherapeutic Agents ◽  
Metastatic Progression ◽  
Matrigel Invasion Assay ◽  
Matrigel Invasion ◽  
Insight Into

e13096 Background: Breast cancers remain the most lethal malignancies amongst women worldwide and the second leading cause of cancer-related mortalities in the US. Subtype heterogeneity and aggressive invasive potential are believed to be the major contributors of these outcomes. Triple-negative breast cancer (TNBC) are notoriously aggressive, difficult-to-treat, and metastatic. Inflammation-driven tumorigenesis has been shown to correlate with cell-free DNA (cfDNA) and other damage-associated molecular patterns (DAMPs) in cancer patient sera. We showed that nucleic-acid scavengers (NAS) can block pro-inflammatory signals elicited by DAMP-activation of innate immune sensors (e.g. toll-like receptors). Treatment with the NAS PAMAM-G3 drastically reduced liver metastatic burden in an immunocompetent murine model of pancreatic cancer. Methods: TNBC cells lines were treated with a cocktail of standard-of-care chemotherapeutic agents and the conditioned media (CM) from these cells served as an in vitro DAMP source. Downstream function of TLR activation was tested via a HEK293-TLR reporter cell line measuring absorbance at 655nm. The in vitro invasive phenotype was tested and quantified using a Transwell-Matrigel invasion assay. Cytokine secretion was measured using a BioLegend cytokine array. Results: TNBC CM greatly increased TNBC cell invasion in vitro and that treatment with the NAS PAMAM-G3 significantly inhibits this effect. Treatment of human monocytes (THP-1) with TNBC CM elicited a strong pro-inflammatory response with elevated levels of IL-8, IL-6, CCL2, and IL-1β. Other biologically immune responders including human PBMCs will be tested to determine the potential impact on the tumor immune microenvironment during tumorigenesis and treatment. Conclusions: To elucidate the mechanism by which this NAS works in these tumor settings, our lab has developed several PAMAM-G3 derivatives, including biotin, IR-, and near-IR fluorophore labeled molecules. These molecules will allow us to capture and characterize DAMPs and do in vivo live imaging experiments to gain insight into NAS PK/PD properties. This insight into NAS capabilities will enhance our understanding of metastatic progression and its interplay with the immune system. Moreover, these principles will aid in the development of novel of anti-metastatic therapies to improve TNBC patient outcomes.

An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer

2021 ◽  
Author(s):  
Hina Qayoom ◽  
Nissar A Wani ◽  
Bader Alshehri ◽  
Manzoor A Mir
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Stem Cells ◽  
The Novel ◽  
Chemotherapeutic Regimen ◽  
Survival Pathways ◽  
Stem Cell Survival ◽  
Preclinical And Clinical Studies ◽  
Insight Into

Triple-negative breast cancer (TNBC) is the most complex, aggressive and fatal subtype of breast cancer. Owing to the lack of targeted therapy and heterogenic nature of TNBC, chemotherapy remains the sole treatment option for TNBC, with taxanes and anthracyclines representing the general chemotherapeutic regimen in TNBC therapy. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. Breast cancer stem cells (BCSCs) are one of the major causes for the development of chemoresistance in TNBC patients. After surviving the chemotherapy damage, the presence of BCSCs results in relapse and recurrence of TNBC. Several pathways are known to regulate BCSCs’ survival, such as the Wnt/β-catenin, Hedgehog, JAK/STAT and HIPPO pathways. Therefore it is imperative to target these pathways in the context of eliminating chemoresistance. In this review we will discuss the novel strategies and various preclinical and clinical studies to give an insight into overcoming TNBC chemoresistance. We present a detailed account of recent studies carried out that open an exciting perspective in relation to the mechanisms of chemoresistance.

Breast Cancer Subtype Classification Using Multi-omics Data Integration Based on Neural Network

2020 ◽  
Vol 47 (9) ◽  
pp. 835-841
Author(s):  
Joungmin Choi ◽  
Jiyoung Lee ◽  
Jieun Kim ◽  
Jihyun Kim ◽  
Heejoon Chae
Keyword(s):  
Breast Cancer ◽  
Neural Network ◽  
Data Integration ◽  
Breast Cancer Subtype ◽  
Omics Data ◽  
Subtype Classification ◽  
Cancer Subtype ◽  
Omics Data Integration

scholarly journals Correction: A Network-Based Data Integration Approach to Support Drug Repurposing and Multi-Target Therapies in Triple Negative Breast Cancer

PLoS ONE ◽  
2017 ◽  
Vol 12 (1) ◽  
pp. e0170363 ◽  
Author(s):  
Francesca Vitali ◽  
Laurie D. Cohen ◽  
Andrea Demartini ◽  
Angela Amato ◽  
Vincenzo Eterno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Data Integration ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Drug Repurposing ◽  
Integration Approach ◽  
Target Therapies

scholarly journals Whole Genome Transcriptome Analysis of the Association between Obesity and Triple Negative Breast Cancer in Caucasian Women

2018 ◽  
Author(s):  
Tarun Mamidi ◽  
Jiande Wu ◽  
Paul B. Tchounwou ◽  
Lucio Miele ◽  
Chindo Hicks
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Postmenopausal Women ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Normal Weight ◽  
Biological Pathways ◽  
Molecular Networks ◽  
Whole Genome ◽  
Caucasian Women

Background: Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with poor outcomes. The molecular basis of TNBC remains poorly understood. The objective of this study was to explore the relationship between obesity and TNBC in premenopausal and postmenopausal Caucasian women using whole genome transcription profiling. Methods: We compared gene expression levels of tumor samples drawn from normal weight, overweight and obese in pre and postmenopausal women diagnosed with TNBC. We performed hierarchical clustering to assess similarity in patterns of gene expression profiles, and conducted network and pathway analysis to identify molecular networks and biological pathways. Results: We discovered gene signatures distinguishing normal weight from obese, normal weight from overweight and overweight from obese individuals in both premenopausal and postmenopausal women. The analysis revealed molecular networks and biological pathways dysregulated in response to obesity. Among the discovered pathways included the unfolded protein response, endoplasmatic reticulum stress, B cell receptor and the autophagy signaling pathways in obese premenopausal women and the integrin, axonal guidance, ERK/MAPK and Glutathione biosynthesis signaling pathways obese postmenopausal women. Conclusions: The results suggest that both overweight and obesity are associated with TNBC, highlighting the need for conformation of these results in independent studies.

scholarly journals Next-Generation Multimodality of Nanomedicine Therapy: Folic Acid Conjugated Copolymer and Folate Receptor Interactions Disrupt Receptor Functionality Resulting in Dual Therapeutic Anti-Cancer Potential in Triple-Negative Breast Cancer

2020 ◽  
Author(s):  
Alexandria DeCarlo ◽  
Cecile Malardier-Jugroot ◽  
Myron R Szewczuk
Keyword(s):  
Breast Cancer ◽  
Folic Acid ◽  
Triple Negative Breast Cancer ◽  
Chemical Engineering ◽  
Triple Negative ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
Expression Levels ◽  
Anti Cancer ◽  
Insight Into

The development of a highly specific drug delivery system (DDS) for anti-cancer therapeutics is an area of intense research focus. Chemical engineering of a “smart” DDS to specifically target tumor cells has gained interest, designed for safer, more efficient, and effective use of chemotherapeutics for the treatment of cancer. However, the selective targeting and choosing the critical cancer surface biomarker are essential for targeted treatments to work. The folic acid receptor alpha (FRalpha) has gained popularity as a potential target in triple-negative breast cancer (TNBC). We have previously reported on a functionalized folic acid (FA)-conjugated amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA) that has the essential features for efficient “smart” DDS. This biocompatible DDS self-assembles in a pH-dependent manner, providing stimuli-responsive, active targeting, extended-release of hydrophobic chemotherapeutic agents, and can effectively penetrate the inner core of 3-dimensional cancer spheroid models. The empty FA-DABA-SMA decreased spheroid volume, revealing a previously unknown mechanism of action. Upon further investigation, a size- and shape-dependent interaction FA-DABA-SMA with FR reduced the expression of p53, the product of the highly mutated TP53 gene, and additional oncogenic c-Myc and STAT3 proteins. Here, we investigated how this copolymer influences FR behavior and disrupting the receptor’s functions. Results indicate that FA-DABA-SMA increases FR expression levels in breast MDA MB-231 cancer cells and disrupting FR signaling by the reduction in HES1 and NOTCH1 protein expression levels. Also, FA-DABA-SMA induces apoptosis and further causes a change in the morphology of the MDA MB-231 cells, as well as significantly reduces their ability to migrate in a Scratch wound assay. Collectively, these findings provide a novel insight into the functionalized FA-DABA-SMA copolymer. The 350 kDa and 20 kDa copolymers actively target FRα to initialize internationalization. However, only the large size and sheet-shaped 350 kDa copolymers disrupt FRα signaling. The significance of these novel findings reveals the intracellular activity of the copolymer that is critically dependent on the size and structural shape. This report offers novel therapeutic insight into a dual mechanism of FA-DABA-SMA copolymer for its therapeutic potential for the treatment of cancer.

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