DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells

Liu, Heshu; Wen, Tao; Zhou, Ying; Fan, Xin; Du, Tan; Gao, Tianbo; Li, Lina; Liu, Jian; Yang, Lei; Yao, Jiannan; Ge, Yang; An, Guangyu

doi:10.1155/2019/1061979

Cited by 20 publications

(29 citation statements)

References 36 publications

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“…By contrast, the staining of DCLK1 was primarily found in the cytoplasm of tumor cells and was easier to quantify. In addition, DCLK1 was reported to play a metastatic-promoting role in breast cancer cell lines and was identified as a cancer stem cell marker in several types of cancer, which indicated potential clinical implications of this marker [18][19][20][21]. Thus, we chose DCLK1 as the marker for the MES subtype.…”

Section: Selection Of Markers For Ihc-based Classificationmentioning

confidence: 99%

Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance

et al. 2020

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Background. Molecular subtyping of triple-negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs. Materials and Methods. By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC-based classifier, and applied it to another two cohorts (n = 183 and 214). Results. We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC-based luminal androgen receptor (IHC-LAR; AR-positive [+]), (b) IHC-based immunomodulatory (IHC-IM; AR-negative [−], CD8+), (c) IHC-based basal-like immune-suppressed (IHC-BLIS; AR−, CD8−, FOXC1+), (d) IHC-based mesenchymal (IHC-MES; AR−, CD8−, FOXC1−, DCLK1 +), and (e) IHC-based unclassifiable (AR−, CD8−, FOXC1−, DCLK1 −). The κ statistic indicated substantial agreement between the IHC-based classification and mRNA-based classification. Multivariate survival analysis suggested that our IHC-based classification was an independent prognostic factor for relapse-free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC-LAR subtype showed relative activation of HER2 pathway. The IHC-IM subtype tended to exhibit an immune-inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC-BLIS subtype showed high expression of a VEGF signature. The IHC-MES subtype displayed activation of JAK/STAT3 signaling pathway. Conclusion. We developed an IHC-based approach to classify TNBCs into molecular subtypes. This IHC-based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes.

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Section: Selection Of Markers For Ihc-based Classificationmentioning

confidence: 99%

Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance

et al. 2020

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“…Dysregulation of DCLK1 in humans and mice is associated with activated pathological cancer stages. DCLK1 is a cancer stem cell (CSC) marker, which promotes initiation, aggressiveness, and metastasis through many pathways, such as the Wnt/β-catenin pathway [ 76 , 77 ]. Thus, the OC-X treatment suppression of DCLK1 in both models implies potential therapeutic applications to control TNBC.…”

Section: Discussionmentioning

confidence: 99%

Comparative Gene Signature of (−)-Oleocanthal Formulation Treatments in Heterogeneous Triple Negative Breast Tumor Models: Oncological Therapeutic Target Insights

et al. 2021

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Triple negative breast cancer (TNBC) heterogeneity and limited therapeutic options confer its phenotypic aggressiveness. The discovery of anti-TNBC natural products with valid molecular target(s) and defined pharmacodynamic profile would facilitate their therapeutic nutraceutical use by TNBC patients. The extra-virgin olive oil (EVOO) is a key Mediterranean diet ingredient. S-(−)-Oleocanthal (OC) leads the bioactive anti-tumor EVOO phenolic ingredients. A previous study reported the solid dispersion formulated OC with (+)-xylitol (OC-X) suppressed the in vivo progression and recurrence of the TNBC MDA-MB-231 cells. This study investigates the ability of OC-X formulation to suppress the in vivo heterogeneous BC initiation and progression utilizing advanced preclinical transgenic MMTV-PyVT and TNBC PDX mouse models. Furthermore, the clustering of the gene expression profiles in MMTV-PyVT and PDX mouse tumors treated with OC-X acquired by a Clariom S microarray analysis identified the distinctly affected genes. Several affected novel signature genes identified in response to OC-X treatments and proved overlapped in both mouse and human tumor models, shedding some lights toward understanding the OC anticancer molecular mechanism and assisting in predicting prospective clinical outcomes. This study provides molecular and preclinical evidences of OC-X potential as a nutraceutical suppressing heterogeneous TNBC model and offers preliminary gene-level therapeutic mechanistic insights.

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“…Subsequently, MACC1 gets phosphorylated by DCLK1. DCLK1 promotes tumor initiation and metastasis formation in different tumor entities including breast, CRC, and pancreas [ 46 , 47 , 48 ]. It was first described as a kinase important for motility of neurons during fetal brain development [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Saffron Crudes and Compounds Restrict MACC1-Dependent Cell Proliferation and Migration of Colorectal Cancer Cells

Güllü

Kobelt

Brim

et al. 2020

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The high mortality rate of colorectal cancer (CRC) patients is directly associated with metastatic dissemination. However, therapeutic options specifically for metastasis are still limited. We previously identified Metastasis-Associated in Colon Cancer 1 (MACC1) as a major causal metastasis-inducing gene. Numerous studies confirmed its value as a biomarker for metastasis risk. We investigated the inhibitory impact of saffron on MACC1-induced cancer cell growth and motility. Saffron crudes restricted the proliferation and migration of MACC1-expressing CRC cells in a concentration- and MACC1-dependent manner. Saffron delays cell cycle progression at G2/M-phase and does not induce apoptosis. Rescue experiments showed that these effects are reversible. Analysis of active saffron compounds elucidated that crocin was the main compound that reproduced total saffron crudes effects. We showed the interaction of MACC1 with the cancer stem cell (CSC) marker DCLK1, which contributes to metastasis formation in different tumor entities. Saffron extracts reduced DCLK1 with crocin being responsible for this reduction. Saffron’s anti-proliferative and anti-migratory effects in MACC1-expressing cells are mediated by crocin through DCLK1 down-regulation. This research is the first identification of saffron-based compounds restricting cancer cell proliferation and motility progression via the novel target MACC1.

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DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells

Cited by 20 publications

References 36 publications

Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance

Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance

Comparative Gene Signature of (−)-Oleocanthal Formulation Treatments in Heterogeneous Triple Negative Breast Tumor Models: Oncological Therapeutic Target Insights

Saffron Crudes and Compounds Restrict MACC1-Dependent Cell Proliferation and Migration of Colorectal Cancer Cells

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