AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer

The era of immunotherapy has seen an insurgence of novel therapies driving oncologic research and the clinical management of the disease. We have previously reported that a combination of chemotherapy (FEC) and oncolytic virotherapy (oHSV-1) can be used to sensitize otherwise non-responsive tumors to immune checkpoint blockade and that tumor-infiltrating B cells are required for the efficacy of our therapeutic regimen in a murine model of triple-negative breast cancer. In the studies herein, we have performed gene expression profiling using microarray analyses and have investigated the differential gene expression between tumors treated with FEC + oHSV-1 versus untreated tumors. In this work, we uncovered a therapeutically driven switch of the myeloid phenotype and a gene signature driving increased tumor cell killing.

Download Full-text

Prognostication of a 13-immune-related-gene signature in patients with early triple-negative breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-020-05874-1 ◽

2020 ◽

Vol 184 (2) ◽

pp. 325-334

Author(s):

Ji-Yeon Kim ◽

Hae Hyun Jung ◽

Insuk Sohn ◽

Sook Young Woo ◽

Hyun Cho ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Gene Signature ◽

Related Gene ◽

Immune Related Gene

Download Full-text

THER-06. GENOMIC AND IMMUNE CHARACTERIZATION OF TRIPLE NEGATIVE BREAST CANCER BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.049 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i11-i12

Author(s):

Benjamin Vincent ◽

Maria Sambade ◽

Shengjie Chai ◽

Marni Siegel ◽

Luz Cuaboy ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Brain Metastases ◽

T Cell Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cell Receptor ◽

Gene Signature ◽

Specific Response ◽

Immune Gene

Abstract INTRODUCTION: Approximately 50% of patients with metastatic triple negative breast cancer (TNBC) will develop brain metastases (BM). Routinely treated with radiotherapy and/or surgery, survival is generally less than one year. There are no approved systemic therapies to treat TNBC BM. We characterized the genomic and immune landscape of TNBC BM to foster the development of effective brain permeable anti-cancer agents, including immunotherapy. EXPERIMENTAL PROCEDURES: A clinically-annotated BCBM biobank of archival tissues was created under IRB approval. DNA (tumor/normal) and RNA (tumor) were extracted from TNBC primaries and BM; whole exome (WES) and RNA sequencing (RNASeq) was performed. Mutations were determined from WES as those co-identified by two variant callers (Strelka|Cadabra). Immune gene signature expression, molecular subtype identification, and T cell receptor repertoires were inferred from RNAseq. RESULTS: 32 TNBC patient tissues (14 primaries, 18 BCBM, 6 primary-BCBM matched), characterized as basal-like by PAM50, were analyzed. Top exome mutation calls included ten genes in ≥19% of BCBMs including TP53, ATM, and PIK3R1, and four genes in ≥18% of primaries including TP53 and PIK3R1. Many immune gene signatures were lower in BM compared to primaries including B cell, dendritic cell, regulatory T cell, and IgG cluster (p< 0.05). A signature of PD-1 inhibition responsiveness was higher in BM compared with primaries (p< 0.05). BCBM T cell receptor repertoires showed higher evenness and lower read count (both p < 0.01) compared to primaries. CONCLUSIONS: TNBC BM compared to primaries that metastasize to the brain show lower immune gene signature expression, higher PD-1 inhibition response signature expression, and T cell receptor repertoire features less characteristic of an active antigen-specific response. Mutations common to TNBC BM and primaries include TP53 and PIK3R1. Given that non-BCBM (i.e. lung and melanoma) show response to checkpoint inhibitors, these findings collectively support further study of immunotherapy for TNBC BM.

Download Full-text

A Six-Epithelial–Mesenchymal Transition Gene Signature May Predict Metastasis of Triple-Negative Breast Cancer

OncoTargets and Therapy ◽

10.2147/ott.s256818 ◽

2020 ◽

Vol Volume 13 ◽

pp. 6497-6509

Author(s):

Li Yuan Wei ◽

Xiao Jun Zhang ◽

Li Wang ◽

Li Na Hu ◽

Xu Dong Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Epithelial Mesenchymal Transition ◽

Gene Signature ◽

Mesenchymal Transition

Download Full-text

Molecular characteristics and metastasis predictor genes of triple-negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1043 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1043-1043

Author(s):

Wen-Hung Kuo ◽

Yao-Yin Chang ◽

Ming-Feng Hou ◽

Eric Y Chuang ◽

King-Jen Chang

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Early Stage ◽

Gene Signature ◽

Breast Cancers ◽

Prognostic Signature ◽

Characteristic Analysis ◽

Disease Etiology ◽

Breast Cancer Outcome

1043 Background: Triple-negative breast cancer(TNBC) is a subtype of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for triple-negative breast cancer are few and recurrence rates are high. Although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis is not yet possible. Methods: Clinicopathological information and microarray data from 157 invasive breast carcinomas were collected at National Taiwan University Hospital from 1995 to 2008. Gene expression data of 51 triple-negative and 106 luminal breast cancers were generated with oligonucleotide microarrays. A prognostic 45-gene signature for triple-negative breast cancer was identified using Student’s t test and receiver operating characteristic analysis. Results: Hierarchical clustering analysis revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A novel 45-gene signature giving 98% predictive accuracy in distant metastasis recurrence was identified in our triple-negative patient cohort. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% CI 1.04-5.06, Cox P = 0.04), outperforming five other published breast cancer prognostic signatures. The prognostic signature was statistically predictive with the node-negative triple-negative patients in the validation cohort. Conclusions: The 45-gene prognostic signature identified in this study revealed that TGF-β signaling in immune/inflammatory regulation may be critically involved in distant metastatic invasion of TNBC. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of metastasis recurrence for early-stage triple-negative patients.

Download Full-text

Interferon-beta represses cancer stem cell properties in triple-negative breast cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713728114 ◽

2017 ◽

Vol 114 (52) ◽

pp. 13792-13797 ◽

Cited By ~ 39

Author(s):

Mary R. Doherty ◽

HyeonJoo Cheon ◽

Damian J. Junk ◽

Shaveta Vinayak ◽

Vinay Varadan ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Triple Negative Breast Cancer ◽

Epithelial To Mesenchymal Transition ◽

Triple Negative ◽

Mammary Epithelial Cells ◽

Gene Expression Signature ◽

Tumor Infiltrating Lymphocytes ◽

Gene Signature ◽

Mesenchymal Transition

Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to-mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-β) led to a less aggressive epithelial/non–CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-β, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-β metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-β reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.

Download Full-text

A Novel Platelet-Related Gene Signature for Predicting the Prognosis of Triple-Negative Breast Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.795600 ◽

2022 ◽

Vol 9 ◽

Author(s):

Jindong Xie ◽

Yutian Zou ◽

Feng Ye ◽

Wanzhen Zhao ◽

Xinhua Xie ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Risk Group ◽

Gene Signature ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Clinical Prognosis

Regarded as the most invasive subtype, triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) proteins. Platelets have recently been shown to be associated with metastasis of malignant tumors. Nevertheless, the status of platelet-related genes in TNBC and their correlation with patient prognosis remain unknown. In this study, the expression and variation levels of platelet-related genes were identified and patients with TNBC were divided into three subtypes. We collected cohorts from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, we constructed a seven-gene signature which classified the two cohorts of patients with TNBC into low- or high-risk groups. Patients in the high-risk group were more likely to have lower survival rates than those in the low-risk group. The risk score, incorporated with the clinical features, was confirmed as an independent factor for predicting the overall survival (OS) time. Functional enrichment analyses revealed the involvement of a variety of vital biological processes and classical cancer-related pathways that could be important to the ultimate prognosis of TNBC. We then built a nomogram that performed well. Moreover, we tested the model in other cohorts and obtained positive outcomes. In conclusion, platelet-related genes were closely related to TNBC, and this novel signature could serve as a tool for the assessment of clinical prognosis.

Download Full-text

A combined hypoxia and immune gene signature for predicting survival and risk stratification in triple-negative breast cancer

Aging ◽

10.18632/aging.203360 ◽

2021 ◽

Author(s):

Xia Yang ◽

Xin Weng ◽

Yajie Yang ◽

Meng Zhang ◽

Yingjie Xiu ◽

...

Keyword(s):

Breast Cancer ◽

Risk Stratification ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Gene Signature ◽

Immune Gene

Download Full-text

A Novel Immune Checkpoint-Related Gene Signature to Predict Overall Survival and Immunotherapy Response in Triple-Negative Breast Cancer

10.21203/rs.3.rs-528492/v1 ◽

2021 ◽

Author(s):

Jingyi Liu ◽

Siyuan Tian ◽

Yuwei Ling ◽

Xinyi Zhang ◽

Yan Li ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Triple Negative ◽

Cox Regression ◽

Expression Profiles ◽

Expression Patterns ◽

Molecular Taxonomy ◽

Gene Signature ◽

Cox Regression Analysis

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective therapeutic targets. Immunotherapy is considered as a novel treatment strategy for TNBC. However, only some patients could benefit from the treatment. Limited studies have comprehensively explored expression patterns and prognostic value of immune checkpoint genes (ICGs) in TNBC. In this study, we downloaded relevant ICGs expression profiles and clinical TNBC data from the Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was employed to develop a multi-gene signature for predicting the prognostic outcome. PDCD1, PDCD1LG2 and KIR3DL2 were identified as hub genes and incorporated into the model. This gene signature could stratify patients into two prognostic subgroups, and unfavorable clinical outcomes were observed in high-risk patients. The predictive performance was assessed by the receiver operating characteristic curves. Moreover, we also analyzed differences in immune status and therapeutic response between both groups. This novel gene signature may be served as a robust prognostic marker, but also an indicator reflecting immunotherapy response.

Download Full-text

Androgen Receptor Highjacks ErbB-2 Nuclear Function to Induce Triple Negative Breast Cancer Growth

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1635 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A804-A804

Author(s):

Agustina Roldán Deamicis ◽

Robert H Oakley ◽

Sergio Andonegui Helguera ◽

Mariela B Lenze ◽

Santiago Madera ◽

...

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Nuclear Migration ◽

Subcellular Fractionation ◽

Gene Signature ◽

Dominant Negative ◽

Cox Regression Analysis

Abstract Triple negative breast cancer (TNBC) has poor prognosis and neither established biomarkers nor therapeutic targets. On the one hand the androgen receptor (AR), a steroid hormone receptor (SR) which is expressed in 10-53% of TNBC and proved to be critical for BC proliferation, has been proposed as a new target in TNBC. On the other hand, we and others have shown that membrane ErbB-2 migrates to the nucleus (nuclear ErbB-2, NErbB-2) where it binds DNA at HER-2 associated sequences (HAS) to regulate BC proliferation and migration. Since we have previously shown a functional interplay between growth factors and SR signaling pathways in BC, we propose the existence of an interaction between AR and ErbB-2 which is involved in NErbB-2+/AR+ BC growth. The experimental model used was the human TNBC cell line MDA-MB-453 which displays high expression levels of AR and NErbB-2. By Western Blot (WB) we found that dihydrotestosterone (DHT) treatment for short times (minutes) did not regulate ErbB-2 phosphorylation status at residues Tyr1221/1222 and 1248 which were constitutively activated. However, DHT led to an increase in ErbB-2 phosphorylation at residue Tyr877 which we have proved to be required for ErbB-2 nuclear migration. The latter effect was blocked by the AR antagonist enzalutamide (enza). Blockage of Src activity with dasatinib inhibited DHT-induced ErbB-2 phosphorylation at Tyr877. By Immunofluorescence and confocal microscopy analyses and subcellular fractionation studies we demonstrated that DHT induced ErbB-2 nuclear migration which was inhibited by enza. By chIP we found that DHT induced ErbB-2 recruitment to a HAS site in ERK5, a gene involved in BC proliferation, and to a HAS site in FKBP5, a classical AR responsive gene. By WB we demonstrated that transfection with an ErbB-2 mutant which is unable to translocate to the nucleus and functions as a dominant negative inhibitor of ErbB-2 nuclear migration (hErbB-2ΔNLS), inhibited FKBP51 up-regulation by DHT. Finally, by microarray and bioinformatics analysis we identified 315 differentially expressed genes (DEGs) in the presence of DHT and NErbB-2 eviction. Enrichment analyses showed that the DEGs belonged to the immune response and interferon pathways. Kaplan-Meier analysis revealed that the expression of 6 genes was significantly associated with overall survival in TNBC patients from the METABRIC cohort: CXCL10, TAP1, STAT1, NMI, HLA-A and NLRC5. Multivariate Cox regression analysis identified the combined expression of the 6 genes as an independent predictor of better clinical outcome in TNBC (HR: 0.56, 95% CI 0.38-0.82, P = 0.003). In conclusion, our findings evidence that DHT-activated AR induces Src-mediated ErbB-2 rapid activation and its migration to the nucleus where it binds to HAS sites in the DNA. Moreover, based on the DEGs of NErbB-2 eviction in presence of DHT we identified a gene signature associated with favorable outcome in TNBC.

Download Full-text