scholarly journals Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer

Cell Reports ◽  
2016 ◽  
Vol 14 (9) ◽  
pp. 2154-2165 ◽  
Author(s):  
Jun Hyoung Park ◽  
Sajna Vithayathil ◽  
Santosh Kumar ◽  
Pi-Lin Sung ◽  
Lacey Elizabeth Dobrolecki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Acid Oxidation

scholarly journals Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer

2016 ◽  
Vol 22 (4) ◽  
pp. 427-432 ◽  
Author(s):  
Roman Camarda ◽  
Alicia Y Zhou ◽  
Rebecca A Kohnz ◽  
Sanjeev Balakrishnan ◽  
Celine Mahieu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Acid Oxidation

Abstract 2673: Inhibition of fatty-acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer

2016 ◽  
Author(s):  
Roman Camarda ◽  
Alicia Y. Zhou ◽  
Rebecca A. Kohnz ◽  
Sanjeev Balakrishnan ◽  
Celine Mahieu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Acid Oxidation

Abstract 1507: Fatty acid oxidation mediated autophagy regulation in triple negative breast cancer

2017 ◽  
Author(s):  
Kwang Hwa Jung ◽  
Jun Hyoung Park ◽  
Tirupataiah Sirupangi ◽  
Sajna Vithayathil ◽  
Lee-Jun Wong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Acid Oxidation

Abstract PD3-05: Inhibition of fatty-acid oxidation as a therapy for triple-negative breast cancer

2016 ◽  
Author(s):  
A Goga ◽  
R Camarda ◽  
AY Zhou ◽  
RA Kohnz ◽  
S Balakrishnan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Acid Oxidation

scholarly journals CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

2017 ◽  
Vol 114 (32) ◽  
pp. E6556-E6565 ◽  
Author(s):  
Heather J. Wright ◽  
Jue Hou ◽  
Binzhi Xu ◽  
Marvin Cortez ◽  
Eric O. Potma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Oxidative Phosphorylation ◽  
Fatty Acid Oxidation ◽  
Triple Negative Breast Cancer ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Metastatic Potential ◽  
Acid Oxidation ◽  
Primary Tumors

Triple-negative breast cancer (TNBC) is notoriously aggressive with high metastatic potential, which has recently been linked to high rates of fatty acid oxidation (FAO). Here we report the mechanism of lipid metabolism dysregulation in TNBC through the prometastatic protein, CUB-domain containing protein 1 (CDCP1). We show that a “low-lipid” phenotype is characteristic of breast cancer cells compared with normal breast epithelial cells and negatively correlates with invasiveness in 3D culture. Using coherent anti-Stokes Raman scattering and two-photon excited fluorescence microscopy, we show that CDCP1 depletes lipids from cytoplasmic lipid droplets (LDs) through reduced acyl-CoA production and increased lipid utilization in the mitochondria through FAO, fueling oxidative phosphorylation. These findings are supported by CDCP1’s interaction with and inhibition of acyl CoA-synthetase ligase (ACSL) activity. Importantly, CDCP1 knockdown increases LD abundance and reduces TNBC 2D migration in vitro, which can be partially rescued by the ACSL inhibitor, Triacsin C. Furthermore, CDCP1 knockdown reduced 3D invasion, which can be rescued by ACSL3 co-knockdown. In vivo, inhibiting CDCP1 activity with an engineered blocking fragment (extracellular portion of cleaved CDCP1) lead to increased LD abundance in primary tumors, decreased metastasis, and increased ACSL activity in two animal models of TNBC. Finally, TNBC lung metastases have lower LD abundance than their corresponding primary tumors, indicating that LD abundance in primary tumor might serve as a prognostic marker for metastatic potential. Our studies have important implications for the development of TNBC therapeutics to specifically block CDCP1-driven FAO and oxidative phosphorylation, which contribute to TNBC migration and metastasis.

scholarly journals 616 CD47 blockade modulates immunosuppressive checkpoint molecules and cellular metabolism to sensitize triple-negative breast cancer tumors to immune checkpoint blockade therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A646-A646
Author(s):  
Elizabeth Stirling ◽  
Adam Wilson ◽  
Katherine Cook ◽  
Alexandra Thomas ◽  
Pierre Triozzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Cell ◽  
Tumor Burden ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Immunosuppressive Cell

BackgroundTriple-negative breast cancer(TNBC) lacks druggable targets and has high metastatic incidence. Immune checkpoint blockades (ICB) are FDA approved for TNBC treatment, but therapeutic response and biomarkers are limited. CD47 is an integral membrane protein overexpressed on cancer cells that alters anti-tumor immunosurveillance, resulting in tumor progression. CD47 is involved in metabolic reprogramming but whether CD47 is a marker of progression and its role in ICB response for TNBC remains unknown.MethodsHuman TNBC biopsies were subjected to immunohistochemical analysis to determine CD47 role in TNBC progression. To determine CD47 impact on tumor burden, a carcinogen-induced TNBC model was performed in female wild type(WT) and cd47 null(cd47-/-) C57Bl/6 mice. To evaluate immune infiltrate signaling, tumors underwent spatial tissue proteomics by multiplexing photo-cleavable antibodies in Formalin-Fixed Paraffin-Embedded samples. An orthotopic EMT-6 murine TNBC model was performed to investigate tumor burden for CD47 monotherapy or in combination with anti-PD-L1 therapy.ResultsHuman matched primary, and metastatic TNBC biopsies increased immunoreactivity to CD47, signifying a potential therapeutic target(n=24). CD47 deficiency in the carcinogen-induced DMBA model decreased tumor incidence, weight, and area compared to WT(n=8/group,*p<0.003). Since CD47 can regulate metabolism, tumors underwent metabolomic analysis. Principal component analysis displayed differentially regulated metabolites between WT and cd47-/- tumors. Decreased carnitine conjugated fatty acids and ketone bodies were observed in cd47-/- tumors compared to WT, suggesting decreased fatty acid availability and/or metabolism(n=9/group,*p<0.05). TNBC cell respiratory measurements validated that targeting CD47 shifted metabolic dependency from fatty acid oxidation to glycolysis(n=3,*p<0.05). Kynurenine/tryptophan pathway metabolites, which catabolize Indoleamine-2,3-dioxygenase(IDO1) and involved in anti-PD-1/PD-L1 resistance, were decreased in cd47-/- tumors compared to WT(n=9/group,*p<0.05). Spatial proteomic analysis determined that cd47-/- tumors had elevated immune cell infiltration(CD45+, CD3+), suggesting CD47 absence enhances tumor immunogenicity and immune-mediated tumor ablation. Multiplexing of photo-cleavable antibodies increased protein expression of immune checkpoint molecules(PD-L1,VISTA,B7-H3,BatF3) and immunosuppressive cell types(CD11b+,Ly6c+) in WT tumors compared to cd47-/-, suggesting CD47 absence limits immunosuppressive signaling(n=16/group,*p<0.05). Since anti-PD-L1 therapies are approved to treat TNBC and WT tumors have PD-L1 upregulation, we examined how targeting CD47 would impact tumor burden of mice receiving anti-PD-L1 therapy. Targeting CD47 or PD-L1 as monotherapy decreased tumor burden; however, in combination it further reduced tumor burden compared to anti-PD-L1 treatment due to increased intratumoral granzyme B secreting cytotoxic T cells(n=4–8/group,*p<0.05).ConclusionsOur data indicates that CD47 may serve as a marker of anti-PD-L1 response, and targeting CD47 enhances immunogenicity and decreases immunosuppressive molecules, sensitizing TNBC tumors to anti-PD-L1 therapy to reduce tumor burden.AcknowledgementsDSP is supported by the NCI R21 (CA249349) and the American Cancer Society Research Scholar Grant (133727-RSG-19-150-01-LIB). ERS is supported by the NIAID Immunology and Pathogenesis T32 Training Grant (T32AI007401).Ethics ApprovalAnimal studies were approved by the Institutional Care and Use Committee, Wake Forest Health Sciences.

scholarly journals EGCG Inhibits Adipose-Derived Mesenchymal Stem Cells Differentiation into Adipocytes and Prevents a STAT3-Mediated Paracrine Oncogenic Control of Triple-Negative Breast Cancer Cell Invasive Phenotype

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1506
Author(s):  
Narjara Gonzalez Suarez ◽  
Sahily Rodriguez Torres ◽  
Amira Ouanouki ◽  
Layal El Cheikh-Hussein ◽  
Borhane Annabi
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cell Differentiation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Stem Cell Differentiation ◽  
Low Grade ◽  
Invasive Phenotype ◽  
Fatty Acid Binding

Obese subjects have an increased risk of developing triple-negative breast cancer (TNBC), in part associated with the chronic low-grade inflammation state. On the other hand, epidemiological data indicates that increased consumption of polyphenol-rich fruits and vegetables plays a key role in reducing incidence of some cancer types. Here, we tested whether green tea-derived epigallocatechin-3-gallate (EGCG) could alter adipose-derived mesenchymal stem cell differentiation into adipocytes, and how this impacts the secretome profile and paracrine regulation of the TNBC invasive phenotype. Here, cell differentiation was performed and conditioned media (CM) from preadipocytes and mature adipocytes harvested. Human TNBC-derived MDA-MB-231 real-time cell migration was performed using the exCELLigence system. Differential gene arrays and RT-qPCR were used to assess gene expression levels. Western blotting was used to assess protein expression and phosphorylation status levels. In vitro vasculogenic mimicry (VM) was assessed with Matrigel. EGCG was found to inhibit the induction of key adipogenic biomarkers, including lipoprotein lipase, adiponectin, leptin, fatty acid synthase, and fatty acid binding protein 4. Increased TNBC-derived MDA-MB-231 cell chemotaxis and vasculogenic mimicry were observed in response to mature adipocytes secretome, and this was correlated with increased STAT3 phosphorylation status. This invasive phenotype was prevented by EGCG, the JAK/STAT inhibitors Tofacitinib and AG490, as well as upon STAT3 gene silencing. In conclusion, dietary catechin-mediated interventions could, in part through the inhibition of adipogenesis and modulation of adipocytes secretome profile, prevent the onset of an obesogenic environment that favors TNBC development.

scholarly journals Triple Negative Breast Cancer: Clinicopathologic Characteristics and Fatty Acid Synthase (Fasn) Expression As a Potential Target

2014 ◽  
Vol 25 ◽  
pp. iv60
Author(s):  
F. Holguin Flores ◽  
G. Vinas ◽  
G. Oliveras ◽  
A. Giro-Perafita ◽  
F. Perez-Bueno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Triple Negative Breast Cancer ◽  
Fatty Acid Synthase ◽  
Triple Negative ◽  
Clinicopathologic Characteristics ◽  
Potential Target
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