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 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

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 Entelon® (Vitis vinifera Seed Extract) Prevents Cancer Metastasis via the Downregulation of Interleukin-1 Alpha in Triple-Negative Breast Cancer Cells

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3644
Author(s):  
Daeun You ◽  
Yisun Jeong ◽  
Sun Young Yoon ◽  
Sung A Kim ◽  
Eunji Lo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Interleukin 1 ◽  
Metastatic Potential ◽  
Cancer Cell Proliferation ◽  
Dependent Pathway

Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.

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 Differential expression of fatty acid desaturase 1 in triple negative breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Differential Expression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Fatty Acid Desaturase ◽  
Differentially Expressed ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Ductal Cells

Women diagnosed with triple negative breast cancer can benefit neither from endocrine therapy nor from HER2-targeted therapies (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding fatty acid desaturase 1, FADS1, when comparing the tumor cells of patients with triple negative breast cancer to normal mammary ductal cells (2). FADS1 was also differentially expressed in bulk tumor in human breast cancer (3). FADS1 mRNA was present at significantly increased quantities in TNBC tumor cells relative to normal mammary ductal cells. Analysis of human survival data revealed that expression of FADS1 in primary tumors of the breast was correlated with recurrence-free survival in patients with basal-like and normal-like subtype cancer, while within triple negative breast cancer, primary tumor expression of FADS1 was correlated with distant metastasis-free survival in patients with basal-like 1 and immunomodulatory subtype disease. FADS1 may be of relevance to initiation, maintenance or progression of triple negative breast cancers. We previously reported (4) that the fatty acid desaturase 2, FADS2, was also among the genes most differentially expressed in triple negative and in early-onset breast cancers (2, 3) in humans. Together, the data suggest that these enzymes (5), their transcriptome-wide differential expression, marked transcriptional up-regulation and accessible catalytic sites may make them suitable for therapeutic targeting.

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