Identification of TENM4 as a Novel Cancer Stem Cell-Associated Molecule and Potential Target in Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is insensitive to endocrine and Her2-directed therapies, making the development of TNBC-targeted therapies an unmet medical need. Since patients with TNBC frequently show a quicker relapse and metastatic progression compared to other breast cancer subtypes, we hypothesized that cancer stem cells (CSC) could have a role in TNBC. To identify putative TNBC CSC-associated targets, we compared the gene expression profiles of CSC-enriched tumorspheres and their parental cells grown as monolayer. Among the up-regulated genes coding for cell membrane-associated proteins, we selected Teneurin 4 (TENM4), involved in cell differentiation and deregulated in tumors of different histotypes, as the object for this study. Meta-analysis of breast cancer datasets shows that TENM4 mRNA is up-regulated in invasive carcinoma specimens compared to normal breast and that high expression of TENM4 correlates with a shorter relapse-free survival in TNBC patients. TENM4 silencing in mammary cancer cells significantly impaired tumorsphere-forming ability, migratory capacity and Focal Adhesion Kinase (FAK) phosphorylation. Moreover, we found higher levels of TENM4 in plasma from tumor-bearing mice and TNBC patients compared to the healthy controls. Overall, our results indicate that TENM4 may act as a novel biomarker and target for the treatment of TNBC.

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Epigenetic Reprogramming and Landscape of Transcriptomic Interactions: Impending Therapeutic Interference of Triple-Negative Breast Cancer in Molecular Medicine

Current Molecular Medicine ◽

10.2174/1566524021666211206092437 ◽

2021 ◽

Vol 21 ◽

Author(s):

Suman Kumar Ray ◽

Sukhes Mukherjee

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Treatment Decision ◽

Copy Number Variations ◽

Molecular Medicine ◽

Breast Cancers ◽

Breast Carcinogenesis

: The mechanisms governing the development and progression of cancers are believed to be the consequence of hereditary deformities and epigenetic modifications. Accordingly, epigenetics has become an incredible and progressively explored field of research to discover better prevention and therapy for neoplasia, especially triple-negative breast cancer (TNBC). It represents 15–20% of all invasive breast cancers and will, in general, have bellicose histological highlights and poor clinical outcomes. In the early phases of triple-negative breast carcinogenesis, epigenetic deregulation modifies chromatin structure and influences the plasticity of cells. It up-keeps the oncogenic reprogramming of malignant progenitor cells with the acquisition of unrestrained selfrenewal capacities. Genomic impulsiveness in TNBC prompts mutations, copy number variations, as well as genetic rearrangements, while epigenetic remodeling includes an amendment by DNA methylation, histone modification, and noncoding RNAs of gene expression profiles. It is currently evident that epigenetic mechanisms assume a significant part in the pathogenesis, maintenance, and therapeutic resistance of TNBC. Although TNBC is a heterogeneous malaise that is perplexing to describe and treat, the ongoing explosion of genetic and epigenetic research will help to expand these endeavors. Latest developments in transcriptome analysis have reformed our understanding of human diseases, including TNBC at the molecular medicine level. It is appealing to envision transcriptomic biomarkers to comprehend tumor behavior more readily regarding its cellular microenvironment. Understanding these essential biomarkers and molecular changes will propel our capability to treat TNBC adequately. This review will depict the different aspects of epigenetics and the landscape of transcriptomics in triple-negative breast carcinogenesis and their impending application for diagnosis, prognosis, and treatment decision with the view of molecular medicine.

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Decoding Immune Heterogeneity of Triple Negative Breast Cancer and Its Association with Systemic Inflammation

Cancers ◽

10.3390/cancers11070911 ◽

2019 ◽

Vol 11 (7) ◽

pp. 911 ◽

Cited By ~ 8

Author(s):

Romero-Cordoba ◽

Meneghini ◽

Sant ◽

Iorio ◽

Sfondrini ◽

...

Keyword(s):

Breast Cancer ◽

Systemic Inflammation ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cytolytic Activity ◽

Local Composition ◽

Immune Infiltrate

Triple negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options. New opportunities are emerging from current comprehensive characterization of tumor immune infiltration and fitness. Therefore, effectiveness of current chemotherapies and novel immunotherapies are partially dictated by host inflammatory and immune profiles. However, further progress in breast cancer immuno-oncology is required to reach a detailed awareness of the immune infiltrate landscape and to determine additional reliable and easily detectable biomarkers. In this study, by analyzing gene expression profiles of 54 TNBC cases we identified three TNBC clusters displaying unique immune features. Deep molecular characterization of immune cells cytolytic-activity and tumor-inflammation status reveled variability in the local composition of the immune infiltrate in the TNBC clusters, reconciled by tumor-infiltrating lymphocytes counts. Platelet-to-lymphocyte ratio (PLR), a blood systemic parameter of inflammation evaluated using pre-surgical blood test data, resulted negatively correlated with local tumoral cytolytic activity and T cell–inflamed microenvironment, whereas tumor aggressiveness score signature positively correlated with PLR values. These data highlighted that systemic inflammation parameters may represent reliable and informative markers of the local immune tumor microenvironment in TNBC patients and could be exploited to decipher tumor infiltrate properties and consequently to select the most appropriate therapies.

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Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

Nature Communications ◽

10.1038/s41467-019-13168-4 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Giada Zurlo ◽

Xijuan Liu ◽

Mamoru Takada ◽

Cheng Fan ◽

Jeremy M. Simon ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Protein Level ◽

Triple Negative ◽

Normal Breast ◽

Cancer Subtypes ◽

Adenylosuccinate Lyase ◽

Non Coding Rna

AbstractProtein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.

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Abstract 4698: Gene expression profiles of triple negative breast cancer epithelial and stromal cells are predictive of treatment response.

10.1158/1538-7445.am2013-4698 ◽

2013 ◽

Author(s):

Bojana Jovanovic ◽

Steven X. Chen ◽

Brian D. Lehmann ◽

Kimberly N. Johnson ◽

Violeta Sanchez ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Treatment Response ◽

Triple Negative Breast Cancer ◽

Stromal Cells ◽

Triple Negative ◽

Expression Profiles ◽

Gene Expression Profiles

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Tumor-infiltrating lymphocytes to predict survival to anthracycline/taxane-based adjuvant chemotherapy in triple negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.1 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 1-1

Author(s):

Qiyun Ou ◽

Yunfang Yu ◽

Xiaoyun Xiao ◽

Baoming Luo

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Meta Analysis ◽

Disease Free Survival ◽

Breast Cancer Subtypes ◽

Her2 Positive ◽

Cancer Subtypes ◽

Infiltrating Lymphocytes

1 Background: Previous clinical data suggested that the tumour-infiltrating lymphocytes (TILs) were predictive in breast cancer treated with adjuvant chemotherapy; however, clinical relevance has yet to be established. We hypothesized that TILs would be associated with overall survival (OS) and disease-free survival (DFS) after anthracycline/taxane-based adjuvant chemotherapy in breast cancer subtypes. Methods: PubMed and EMBASE were searched until March 2017 for studies that investigated the association of TILs with survival for anthracycline/taxane-based adjuvant chemotherapy in breast cancer. OS and DFS were combined using random-effects meta-analysis and calculated as combined hazard ratio (HR) with 95% credible intervals (CIs). The PROSPERO registry number is CRD42017072133. Results: Twelve studies comprising 9,023 patients were eligible for analysis. Six were prospective adjuvant trials (n = 7686) and six were retrospective studies (n = 1337). Pooled analysis indicated that high TILs have no significant predictive association in overall population (DFS, HR = 0.87, 95% CI, 0.70 – 1.08; OS, HR = 0.98, 95% CI, 0.89 – 1.07), Luminal A/B (DFS, HR = 0.99, 95% CI, 0.94 – 1.04; OS, HR = 1.01, 95% CI, 0.92 – 1.12), and HER2–positive patients (DFS, HR = 0.84, 95% CI, 0.71 – 1.00; OS, HR = 0.89, 95% CI, 0.77 – 1.02), but were related to improved DFS (HR, 0.81; 95% CI, 0.73 – 0.89) and OS (HR, 0.74; 95% CI, 0.66 – 0.84) in triple negative breast cancer (TNBC) patients. Additionally, increasing TILs were not significantly associated with reduced risk of relapse in HER2-positive patient through adjuvant trastuzumab (HR, 0.97; 95% CI, 0.93 – 1.01). Conclusions: This meta-analysis provides an evidence that TILs predicts survival to anthracycline/taxane-based adjuvant chemotherapy in TNBC patients and suggests that predictive benefit seemed to be influenced by breast cancer subtypes as well.

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Analysis of gene expression patterns in triple negative breast cancer: MERTK and WHSC1L1.

10.31219/osf.io/7c9pu ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Black Women ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Subtype ◽

Expression Profiles ◽

Expression Patterns ◽

Gene Expression Profiles ◽

Primary Tumors

Triple negative breast cancer (TNBC) shares overlap with the basal molecular subtype of breast cancer and is more frequently diagnosed in African-American (black) women for reasons not understood (1,2). To understand genes whose expression may be of pertinence to the development or progression of triple negative breast cancer, we mined published microarray data (3,4) comparing global gene expression profiles of TNBC histology groups, identifying genes whose expression changed the least between among TNBCs, suggesting that these genes may be important for TNBC biology. We identified the MER proto-oncogene tyrosine kinase MERTK and the Wolf-Hirschhorn syndrome candidate 1-like 1 WHSC1L1 among the genes whose expression differed the least when comparing TNBC cases and subtypes. In another dataset, MERTK and WHSCL1 were found to be differentially expressed in TNBC when comparing primary tumors of the breast to normal breast tissue. Kaplan-Meier survival analysis revealed that expression levels of MERTK and WHSCL1 correlated with survival outcomes in human breast cancer, and that this correlation differed based on race of the patient. MERTK and WHSCL1 may be of relevance in understanding the etiology or progression of triple negative breast cancer.

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Computational Analysis of mRNA Expression Profiles Identifies theITGFamily andPIK3R3as Crucial Genes for Regulating Triple Negative Breast Cancer Cell Migration

BioMed Research International ◽

10.1155/2014/536591 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Sukhontip Klahan ◽

Mei-Shin Wu ◽

Edward Hsi ◽

Chi-Cheng Huang ◽

Ming-Feng Hou ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Expression Profiles ◽

Growth Factor Receptor ◽

Cancer Subtypes ◽

Asian Populations ◽

Epidermal Growth ◽

Microarray Datasets ◽

Express Estrogen Receptor

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2/neu). TNBC has worse clinical outcomes than other breast cancer subtypes. However, the key molecules and mechanisms of TNBC migration remain unclear. In this study, we compared two normalized microarray datasets from GEO database between Asian (GSE33926) and non-Asian populations (GSE46581) to determine the molecules and common pathways in TNBC migration. We demonstrated that 16 genes in non-Asian samples and 9 genes in Asian samples are related to TNBC migration. In addition, our analytic results showed that 4 genes,PIK3R3, ITGB1, ITGAL, andITGA6, were involved in the regulation of actin cytoskeleton. Our results indicated potential genes that link to TNBC migration. This study may help identify novel therapeutic targets for drug development in cancer therapy.

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Gene Expression Profiles Induced by High-dose Ionizing Radiation in MDA-MB-231 Triple-negative Breast Cancer Cell Line

Cancer Genomics & Proteomics ◽

10.21873/cgp.20130 ◽

2019 ◽

Vol 16 (4) ◽

pp. 257-266 ◽

Cited By ~ 2

Author(s):

VALENTINA BRAVATÀ ◽

FRANCESCO PAOLO CAMMARATA ◽

LUIGI MINAFRA ◽

ROSA MUSSO ◽

GAIA PUCCI ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Ionizing Radiation ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cell Line ◽

Triple Negative ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cancer Cell Line ◽

High Dose

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Drivers and suppressors of triple-negative breast cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2104162118 ◽

2021 ◽

Vol 118 (33) ◽

pp. e2104162118

Author(s):

Wanfu Wu ◽

Margaret Warner ◽

Li Wang ◽

Wei-Wei He ◽

Ruipeng Zhao ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Acid Metabolite ◽

Fatty Acid Metabolite ◽

Unexpected Findings ◽

Cytochrome P450 Family ◽

Formalin Fixed

To identify regulators of triple-negative breast cancer (TNBC), gene expression profiles of malignant parts of TNBC (mTNBC) and normal adjacent (nadj) parts of the same breasts have been compared. We are interested in the roles of estrogen receptor β (ERβ) and the cytochrome P450 family (CYPs) as drivers of TNBC. We examined by RNA sequencing the mTNBC and nadj parts of five women. We found more than a fivefold elevation in mTNBC of genes already known to be expressed in TNBC: BIRC5/survivin, Wnt-10A and -7B, matrix metalloproteinases (MMPs), chemokines, anterior gradient proteins, and lysophosphatidic acid receptor and the known basal characteristics of TNBC, sox10, ROPN1B, and Col9a3. There were two unexpected findings: 1) a strong induction of CYPs involved in activation of fatty acids (CYP4), and in inactivation of calcitriol (CYP24A1) and retinoic acid (CYP26A1); and 2) a marked down-regulation of FOS, FRA1, and JUN, known tethering partners of ERβ. ERβ is expressed in 20 to 30% of TNBCs and is being evaluated as a target for treating TNBC. We used ERβ+ TNBC patient-derived xenografts in mice and found that the ERβ agonist LY500703 had no effect on growth or proliferation. Expression of CYPs was confirmed by immunohistochemistry in formalin-fixed and paraffin-embedded (FFPE) TNBC. In TNBC cell lines, the CYP4Z1-catalyzed fatty acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) increased proliferation, while calcitriol decreased proliferation but only after inhibition of CYP24A1. We conclude that CYP-mediated pathways can be drivers of TNBC but that ERβ is unlikely to be a tumor suppressor because the absence of its main tethering partners renders ERβ functionless on genes involved in proliferation and inflammation.

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