scholarly journals LncRNA HCP5 Encoding Protein Regulates Ferroptosis To Promote The Progression of Triple Negative Breast Cancer

2021 ◽  
Author(s):  
Xiao Tong ◽  
Jiani Xing ◽  
Haizhou Liu ◽  
Shunheng Zhou ◽  
Yue Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Encoding Protein ◽  
Coding Capacity

Abstract Background Long non-coding RNAs (lncRNAs) is widely described as a class of RNA longer than 200 nucleotides without encoding capability. But recent years, more and more open reading frames (ORFs) have been found in lncRNAs which indicate they have coding capacity. But the mechanisms of the encoding products in cancer are mostly unknown. We have previously shown lncRNA HCP5 is an oncogene in triple negative breast cancer (TNBC), and the aim of the current study was to investigate if lncRNA HCP5 encoding protein promotes TNBC by regulating ferroptosis. Methods We use bioinformatics to predict coding capacity. Molecular biology experiments and the xenograft assay in nude mice to study the mechanism of lncRNA HCP5 encoding protein. And the protein expression was evaluated in a tissue microarray of 140 invasive breast tumors and 45 pared precancerous breast tissues. Association between the protein expression and clinicopathologic features of breast cancer patients was analyzed. Results In this study, we identify that ORF in lncRNA HCP5 can encode a conserved protein with 132-amino acid. The protein, which is named HCP5-132aa, promotes TNBC growth. Mechanistically, the HCP5-132aa regulates GPX4 expression and lipid ROS level through ferroptosis pathway to promote TNBC progression. HCP5-132aa ORF knockdown synergizes with ferroptosis activators in vitro and in vivo. Breast cancer patients with high levels of HCP5-132aa have poorer prognosis. Conclusions Our study indicates that overexpression of lncRNA HCP5 encoding protein is a critical oncogenic event in TNBC. Our findings uncover a regulatory mechanism of ferroptosis in TNBC orchestrated by a protein encoded by an lncRNA.

scholarly journals High ERK Protein Expression Levels Correlate with Shorter Survival in Triple‐Negative Breast Cancer Patients

2012 ◽  
Vol 17 (6) ◽  
pp. 766-774 ◽  
Author(s):  
Chandra Bartholomeusz ◽  
Ana M. Gonzalez‐Angulo ◽  
Ping Liu ◽  
Naoki Hayashi ◽  
Ana Lluch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Expression Levels

scholarly journals Overexpression of miRNA-3613-3p Enhances the Sensitivity of Triple Negative Breast Cancer to CDK4/6 Inhibitor Palbociclib

2020 ◽  
Vol 10 ◽  
Author(s):  
Yuanhang Yu ◽  
Han Liao ◽  
Rong Xie ◽  
Yue Zhang ◽  
Renjing Zheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Progesterone Receptors ◽  
Predictive Biomarker ◽  
Inhibitory Effect ◽  
Breast Cancer Patients ◽  
Ki 67

Triple negative breast cancer (TNBC) is characterized by lack of expression of the estrogen and progesterone receptors and HER2, which are common therapeutic targets. CDK4/6 inhibitor Palbociclib has been approved as an anti-cancer agent for breast cancer. However, identifying biomarkers that predict the response to Palbociclib has always been a challenge for molecular targeted therapy. In this study, we identify microRNA as a hallmark in TNBC patients and explore if miR-3613-3p might serve as a tumor suppressor biomarker for triple negative breast cancer patients and if overexpression of miR-3613-3p could enhance the sensitivity of TNBC cells to Palbociclib. We show that the expression of miR3613-3p was down-regulated in TNBC tumors and cells, and the overexpression of miR-3613-3p in patients’ tumor tissues was clinically and pathologically correlated with favorable prognosis, such as smaller tumor size and the lower Ki-67. In vitro, overexpression of miR-3613-3p inhibited cell proliferation, induced G1 cell-cycle arrest, and enhanced the sensitivity of TNBC cells to Palbociclib treatment. In vivo study revealed that overexpression of miR-3613-3p inhibited TNBC tumorigenesis and exerted a significant inhibitory effect of Palbociclib on MDA-MB-231 cells. Mechanically, SMAD2 and EZH2 were found to be two direct targets of miR-3613-3p and mediate the proliferation of TNBC cells and the sensitivity of the cells to Palbociclib through inducing cellular senescence. Our findings suggested that miR-3613-3p acts as a cancer-suppressor miRNA in TNBC. Moreover, our study showed that miR-3613-3p might be used as a predictive biomarker for the response of TNBC to Palbociclib.

scholarly journals IDO Inhibition Facilitates Antitumor Immunity of Vγ9Vδ2 T Cells in Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Peng Li ◽  
Ruan Wu ◽  
Ke Li ◽  
Wenhui Yuan ◽  
Chuqian Zeng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Γδ T Cells ◽  
Clinical Samples ◽  
Breast Cancer Patients ◽  
Vγ9vδ2 T Cells

Triple-negative breast cancer (TNBC) escape from immune-mediated destruction was associated with immunosuppressive responses that dampened the activation of tumor-infiltrating CD8 and γδ T cells. TNBC had a higher level of programmed cell death 1-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO), compared with other breast cancer subtypes. But, clinical studies have revealed that the response rate of PD-1/PD-L1 antibody for TNBC treatment was relatively low. However, the antitumor responses of human Vγ9Vδ2 T cells or IDO inhibitor in TNBC treatment are unknown. In this study, we found that IDO1 and PD-L1 were highly expressed in TNBC patients. Analysis of the clinical samples demonstrated that Vγ9Vδ2 T cells became exhausted in triple-negative breast cancer patients. And Vγ9Vδ2 T cells combined with αPD-L1 could not further enhance their antitumor responses in vitro and in vivo. However, Vγ9Vδ2 T cells combined with IDO1 inhibitor 1-Methyl-L-tryptophan (1-MT) or Lindrostat showed substantial inhibitory effects on MDA-MB-231 tumor cells. Finally, we found that IDO1 inhibitor promoted T cell’s cytotoxicity by enhancing perforin production. These results converged to suggest the potential application of Vγ9Vδ2 T cells treated with IDO1 inhibitor for TNBC therapy.

Ex-vivo analysis of the isoform selective histone deacetylase inhibitor entinostat in triple-negative breast cancer tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14597-e14597
Author(s):  
P. Ordentlich ◽  
L. Tee ◽  
Y. Huynh ◽  
S. Mee ◽  
H. Mamuszka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Breast Tumor ◽  
Histone Deacetylase Inhibitor ◽  
Triple Negative ◽  
Breast Tumors ◽  
Breast Cancer Patients ◽  
Deacetylase Inhibitor

e14597 Background: Triple-negative (ER, PR, HER2 negative) breast cancer represents an unmet need for which novel agents and approaches are essential. Entinostat is an orally available, class 1 isoform selective histone deacetylase inhibitor currently in multiple phase 2 clinical studies including advanced NSCLC and breast cancer. Studies in vitro and in vivo in the triple negative cell line model MDA-MB-231 have established single agent activity of entinostat in inhibiting tumor growth as well preventing bone metastases. In addition, entinostat induces expression of ERα in MDA-MB-231 in vivo and is synergistic with endocrine therapy agents to inhibit tumor growth of ER negative cancer cells. The aim of these studies was to confirm the activity of entinostat in triple negative breast cancers using human breast tumor explants. Methods: Cytotoxicity of entinostat was determined by the Oncotech Extreme Drug Resistance (EDR) proliferation assay using ten cryopreserved breast tumor explants known to lack estrogen receptor, progesterone receptor and HER2/neu expression (i.e. Triple negative) by immunohistochemistry. Results: Dose response curves of entinostat were analyzed and compared to paclitaxel at 2.45 μM in ten triple negative breast tumor explants in the EDR assay. Entinostat was broadly effective in all of the tumors tested, with most samples showing dose-dependent response for the range of concentrations analyzed (0.003 - 10 μM). Two of the breast tumors that were most sensitive to entinostat (IC50 30- 100nM) were also sensitive to paclitaxel. In contrast, entinostat effectively inhibited (IC50 10–270nM) the growth of eight of the tumors that were resistant to paclitaxel (i.e. < 50% growth inhibition). Overall, all breast tumors tested were sensitive to entinostat at clinically achievable concentrations regardless of paclitaxel resistance indicating entinostat may improve the treatment outcome of triple negative breast cancer patients. Conclusions: Entinostat is an effective agent at inhibiting the growth of triple negative breast tumors with clinically relevant IC50's ranging from 10nM to 270nM. A pre-surgical clinical study to assess the activity of entinostat in triple negative breast cancer patients is planned. [Table: see text]

scholarly journals GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002383
Author(s):  
Jin-Li Wei ◽  
Si-Yu Wu ◽  
Yun-Song Yang ◽  
Yi Xiao ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Sequencing Data ◽  
Aryl Hydrocarbon

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

scholarly journals Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sofia M. Saraiva ◽  
Carlha Gutiérrez-Lovera ◽  
Jeannette Martínez-Val ◽  
Sainza Lores ◽  
Belén L. Bouzo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Skin Barrier ◽  
Zebrafish Embryos ◽  
Biorelevant Media

AbstractTriple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

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