TUFT1 Promotes Triple Negative Breast Cancer Metastasis, Stemness, and Chemoresistance by Up-Regulating the Rac1/β-Catenin Pathway

Li, Weiguang; Chen, Guanglei; Sun, Lisha; Zhang, Yue; Han, Jianjun; Dai, Yuna; He, Jianchao; Shi, Sufang; Chen, Bin

doi:10.3389/fonc.2019.00617

Cited by 28 publications

(25 citation statements)

References 68 publications

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“…Chemoresistance remains the primary challenge in the treatment of TNBC, resulting in a poor prognosis. Although anthracycline and taxane‐based standard chemotherapy can achieve significant responses, more than 50% of patients with TNBC, especially those with advanced‐stage disease, suffer a quick relapse, leading to patient death [44]. Recently, gene expression analyses of residual drug‐refractory breast tumors following chemotherapy revealed enrichment of CSC‐like gene expression signatures, suggesting a causal association between CSCs and chemoresistance [45].…”

Section: Discussionmentioning

confidence: 99%

BOP1 confers chemoresistance of triple‐negative breast cancer by promoting CBP‐mediated β‐catenin acetylation

Huang³

et al. 2021

The Journal of Pathology

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Chemoresistance is a major obstacle to the treatment of triple‐negative breast cancer (TNBC), which has a poor prognosis. Increasing evidence has demonstrated the essential role of cancer stem cells (CSCs) in the process of TNBC chemoresistance. However, the underlying mechanism remains unclear. In the present study, we report that block of proliferation 1 (BOP1) serves as a key regulator of chemoresistance in TNBC. BOP1 expression was significantly upregulated in chemoresistant TNBC tissues, and high expression of BOP1 correlated with shorter overall survival and relapse‐free survival in patients with TNBC. BOP1 overexpression promoted, while BOP1 downregulation inhibited the drug resistance and CSC‐like phenotype of TNBC cells in vitro and in vivo. Moreover, BOP1 activated Wnt/β‐catenin signaling by increasing the recruitment of cyclic AMP response element‐binding protein (CBP) to β‐catenin, enhancing CBP‐mediated acetylation of β‐catenin, and increasing the transcription of downstream stemness‐related genes CD133 and ALDH1A1. Notably, treating with the β‐catenin/CBP inhibitor PRI‐724 induced an enhancement of chemotherapeutic response of paclitaxel in BOP1‐overexpressing TNBC cells. These findings indicate that BOP1 is involved in chemoresistance development and might serve as a prognostic marker and therapeutic target in TNBC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

BOP1 confers chemoresistance of triple‐negative breast cancer by promoting CBP‐mediated β‐catenin acetylation

Huang³

et al. 2021

The Journal of Pathology

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“…Finally, several functional interactions among the “core 1q-OverUpT” genes could be tracked to well-described molecular changes supporting cancer progression, such as SLC30A1 that encodes a zinc transporter [ 100 ], Trim46 that (together with 1q-located TRIM11 and TRIM17) belongs to a large gene family involved in breast cancer [ 101 , 102 ], and TUFT1 (Tuftelin) that promotes triple negative breast cancer metastasis and stemness by upregulating the Rac1/beta-catenin pathway [ 103 ].…”

Section: Discussionmentioning

confidence: 99%

Aberrations of Chromosomes 1 and 16 in Breast Cancer: A Framework for Cooperation of Transcriptionally Dysregulated Genes

Privitera

Barresi

Condorelli

2021

Cancers

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Derivative chromosome der(1;16), isochromosome 1q, and deleted 16q—producing arm-level 1q-gain and/or 16q-loss—are recurrent cytogenetic abnormalities in breast cancer, but their exact role in determining the malignant phenotype is still largely unknown. We exploited The Cancer Genome Atlas (TCGA) data to generate and analyze groups of breast invasive carcinomas, called 1,16-chromogroups, that are characterized by a pattern of arm-level somatic copy number aberrations congruent with known cytogenetic aberrations of chromosome 1 and 16. Substantial differences were found among 1,16-chromogroups in terms of other chromosomal aberrations, aneuploidy scores, transcriptomic data, single-point mutations, histotypes, and molecular subtypes. Breast cancers with a co-occurrence of 1q-gain and 16q-loss can be distinguished in a “low aneuploidy score” group, congruent to der(1;16), and a “high aneuploidy score” group, congruent to the co-occurrence of isochromosome 1q and deleted 16q. Another three groups are formed by cancers showing separately 1q-gain or 16q-loss or no aberrations of 1q and 16q. Transcriptome comparisons among the 1,16-chromogroups, integrated with functional pathway analysis, suggested the cooperation of overexpressed 1q genes and underexpressed 16q genes in the genesis of both ductal and lobular carcinomas, thus highlighting the putative role of genes encoding gamma-secretase subunits (APH1A, PSEN2, and NCSTN) and Wnt enhanceosome components (BCL9 and PYGO2) in 1q, and the glycoprotein E-cadherin (CDH1), the E3 ubiquitin-protein ligase WWP2, the deubiquitinating enzyme CYLD, and the transcription factor CBFB in 16q. The analysis of 1,16-chromogroups is a strategy with far-reaching implications for the selection of cancer cell models and novel experimental therapies.

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“…In our recently published article, we evaluated the role of TUFT1 in promoting the metastasis of TNBC cells in vivo and in vitro [13]. To investigate whether Rab5 is a primary target of TUFT1 in the regulation of TNBC metastasis, endogenous Rab5 was inhibited in TUFT1-transfected MDA-MB-231 ( p < 0.01; Fig.…”

Section: Resultsmentioning

confidence: 99%

TUFT1 promotes metastasis and chemoresistance in triple negative breast cancer through the TUFT1/Rab5/Rac1 pathway

Han

Shi

et al. 2019

Cancer Cell Int

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Background Triple negative breast cancer (TNBC) is a breast cancer (BC) subtype that is characterized by its strong invasion and a high risk of metastasis. However, the specific mechanisms underlying these phenotypes are unclear. TUFT1 plays an important role in BC and impacts the proliferation and survival of BC cells. Recent studies have shown that TUFT1 mediates intracellular lysosome localization and vesicle transport by regulating Rab GTPase, but the relevance of this activity in TNBC is unknown. Therefore, our aim was to systematically study the role of TUFT1 in the metastasis and chemoresistance of TNBC. Methods We measured TUFT1, Rab5-GTP, and Rac1-GTP expression levels in samples of human TNBC by immunohistochemistry (IHC) and conducted univariate and multivariate analyses. shRNA-mediated knockdown and overexpression, combined with transwell assays, co-immunoprecipitation, a nude mouse xenograft tumor model, and GTP activity assays were used for further mechanistic studies. Results TUFT1 expression was positively correlated with Rab5-GTP and Rac1-GTP in the TNBC samples, and co-expression of TUFT1 and Rab5-GTP predicted poor prognosis in TNBC patients who were treated with chemotherapy. Mechanism studies showed that TUFT1 could activate Rab5 by binding to p85α, leading to activation of Rac1 through recruitment of Tiam1, and concurrent down-regulation of the NF-κB pathway and proapoptotic factors, ultimately promoting metastasis and chemoresistance in TNBC cells. Conclusions Our findings suggest that the TUFT1/Rab5/Rac1 pathway may be a potential target for the effective treatment of TNBC.

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TUFT1 Promotes Triple Negative Breast Cancer Metastasis, Stemness, and Chemoresistance by Up-Regulating the Rac1/β-Catenin Pathway

Cited by 28 publications

References 68 publications

BOP1 confers chemoresistance of triple‐negative breast cancer by promoting CBP‐mediated β‐catenin acetylation

BOP1 confers chemoresistance of triple‐negative breast cancer by promoting CBP‐mediated β‐catenin acetylation

Aberrations of Chromosomes 1 and 16 in Breast Cancer: A Framework for Cooperation of Transcriptionally Dysregulated Genes

TUFT1 promotes metastasis and chemoresistance in triple negative breast cancer through the TUFT1/Rab5/Rac1 pathway

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