scholarly journals Lung-Derived Selectins Enhance Metastatic Behavior of Triple Negative Breast Cancer Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1580
Author(s):  
Sami U. Khan ◽  
Ying Xia ◽  
David Goodale ◽  
Gabriella Schoettle ◽  
Alison L. Allan
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Ex Vivo ◽  
Metastatic Progression ◽  
Wild Type ◽  
Potential Therapeutic Target ◽  
Metastatic Behavior

The lung is one of the deadliest sites of breast cancer metastasis, particularly for triple negative breast cancer (TNBC). We have previously shown that the lung produces several soluble factors that may enhance the metastatic behavior of TNBC, including E-, L-, and P-selectin. In this paper, we hypothesize that lung-derived selectins promote TNBC metastatic behavior and may serve as a potential therapeutic target. Lungs were isolated from mice and used to generate lung-conditioned media (CM). Lung-derived selectins were immunodepleted and TNBC migration and proliferation were assessed in response to native or selectin-depleted lung-CM. A 3D ex vivo pulmonary metastasis assay (PuMA) was used to assess the metastatic progression of TNBC in the lungs of wild-type versus triple-selectin (ELP-/-) knockout mice. We observed that individual lung-derived selectins enhance in vitro migration (p ≤ 0.05), but not the proliferation of TNBC cells, and that ex vivo metastatic progression is reduced in the lungs of ELP-/- mice compared to wild-type mice (p ≤ 0.05). Treatment with the pan-selectin inhibitor bimosiamose reduced in vitro lung-specific TNBC migration and proliferation (p ≤ 0.05). Taken together, these results suggest that lung-derived selectins may present a potential therapeutic target against TNBC metastasis. Future studies are aimed at elucidating the pro-metastatic mechanisms of lung-derived selectins and developing a lung-directed therapeutic approach.

scholarly journals CBP/β-Catenin/FOXM1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 525 ◽  
Author(s):  
Alexander Ring ◽  
Cu Nguyen ◽  
Goar Smbatyan ◽  
Debu Tripathy ◽  
Min Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Drug Resistance ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Creb Binding Protein ◽  
Novel Therapeutic

Background: Triple negative breast cancers (TNBCs) are an aggressive BC subtype, characterized by high rates of drug resistance and a high proportion of cancer stem cells (CSC). CSCs are thought to be responsible for tumor initiation and drug resistance. cAMP-response element-binding (CREB) binding protein (CREBBP or CBP) has been implicated in CSC biology and may provide a novel therapeutic target in TNBC. Methods: RNA Seq pre- and post treatment with the CBP-binding small molecule ICG-001 was used to characterize CBP-driven gene expression in TNBC cells. In vitro and in vivo TNBC models were used to determine the therapeutic effect of CBP inhibition via ICG-001. Tissue microarrays (TMAs) were used to investigate the potential of CBP and associated proteins as biomarkers in TNBC. Results: The CBP/ß-catenin/FOXM1 transcriptional complex drives gene expression in TNBC and is associated with increased CSC numbers, drug resistance and poor survival outcome. Targeting of CBP/β-catenin/FOXM1 with ICG-001 eliminated CSCs and sensitized TNBC tumors to chemotherapy. Immunohistochemistry of TMAs demonstrated a significant correlation between FOXM1 expression and TNBC subtype. Conclusion: CBP/β-catenin/FOXM1 transcriptional activity plays an important role in TNBC drug resistance and CSC phenotype. CBP/β-catenin/FOXM1 provides a molecular target for precision therapy in triple negative breast cancer and could form a rationale for potential clinical trials.

c-Met as a potential therapeutic target in triple negative breast cancer

2020 ◽  
pp. 295-326
Author(s):  
Sapana Sameer Chaudhary ◽  
Sameer Choudhary ◽  
Sakshi Rawat ◽  
Gouri Ahir ◽  
Anwar L. Bilgrami ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Potential Therapeutic Target

scholarly journals Simultaneous CK2/TNIK/Dyrk1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease

2020 ◽  
Author(s):  
Katsutoshi Sato ◽  
Amol Padgaonkar ◽  
Stacey Baker ◽  
Stephen Cosenza ◽  
Olga Rechkoblit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Early Stage ◽  
Strong Predictor ◽  
Metastatic Progression ◽  
Current Standard ◽  
Early Stage Disease

Abstract Triple negative breast cancer (TNBC) remains clinically challenging as patients have heterogeneous responses to current standard of care therapies. Chemotherapy sensitivity is a strong predictor of long-term outcomes for patients, and incomplete response of early stage disease to chemotherapy treatment is associated with a much higher risk of disease relapse and metastatic progression, often occurring within a short time from initial diagnosis. Therefore, treatment strategies that target chemotherapy-resistant TNBC and/or enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSC) have been proposed to represent a chemotherapy-resistant subpopulation within the tumor which are also responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. We have identified a novel multi-kinase inhibitor 108600 from a screen for inhibitors of this TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of the BCSC population. Treatment with 108600 induces G2M arrest and eventual apoptosis of TNBC cells in vitro and of TNBC xenografts in vivo, and overcomes chemotherapy (paclitaxel) resistance of triple negative patient-derived xenografts (PDX). Finally, treatment with 108600 and chemotherapy suppressed the growth of already established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.

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.

Abstract 4373: LRP5: a potential therapeutic target in triple-negative breast cancer.

2013 ◽  
Author(s):  
Sylvie Maubant ◽  
Virginie Maire ◽  
Bruno Tesson ◽  
David Gentien ◽  
Bérengère Marty-Prouvost ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Potential Therapeutic Target
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