FAT4 functions as a tumor suppressor in triple-negative breast cancer

Hou, Lingmi; Chen, Maoshan; Zhao, Xiaobo; Li, Jingdong; Deng, Shumin; Hu, Jiani; Yang, Hongwei; Jiang, Jun

doi:10.1007/s13277-016-5421-3

Cited by 28 publications

(26 citation statements)

References 18 publications

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“…NF1 is a well-known tumor suppressor gene and it was mutated in 11% of the samples and ZFHX4 in 21% of the samples. We identified SNVs in the cadherin repeat domains of FAT family genes, i.e., FAT1 and FAT4 in 21% samples, which are functionally characterized as tumor suppressor genes in multiple cancers including ESCC (13,(32)(33)(34). In concordance with ESCC genomic profiles from Chinese and Japanese cohorts, we identified several previously reported recurrently mutated genes ( Supplementary Table 4).…”

Section: Somatic Mutation Spectrum Of Esophageal Squamous Cell Carcinomasupporting

confidence: 70%

Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort

et al. 2020

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Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype of esophageal cancer in India. Cigarette smoking and chewing tobacco are known risk factors associated with ESCC. However, genomic alterations associated with ESCC in India are not well-characterized. In this study, we carried out exome sequencing to characterize the mutational landscape of ESCC tumors from subjects with a varied history of tobacco usage. Whole exome sequence analysis of ESCC from an Indian cohort revealed several genes that were mutated or had copy number changes. ESCC from tobacco chewers had a higher frequency of C:G > A:T transversions and 2-fold enrichment for mutation signature 4 compared to smokers and non-users of tobacco. Genes, such as TP53, CSMD3, SYNE1, PIK3CA, and NOTCH1 were found to be frequently mutated in Indian cohort. Mutually exclusive mutation patterns were observed in PIK3CA-NOTCH1, DNAH5-ZFHX4, MUC16-FAT1, and ZFHX4-NOTCH1 gene pairs. Recurrent amplifications were observed in 3q22-3q29, 11q13.3-q13.4, 7q22.1-q31.1, and 8q24 regions. Approximately 53% of tumors had genomic alterations in PIK3CA making this pathway a promising candidate for targeted therapy. In conclusion, we observe enrichment of mutation signature 4 in ESCC tumors from patients with a history of tobacco chewing. This is likely due to direct exposure of esophagus to tobacco carcinogens when it is chewed and swallowed. Genomic alterations were frequently observed in PIK3CA-AKT pathway members independent of the history of tobacco usage. PIK3CA pathway can be potentially targeted in ESCC which currently has no effective targeted therapeutic options.

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Section: Somatic Mutation Spectrum Of Esophageal Squamous Cell Carcinomasupporting

confidence: 70%

Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort

et al. 2020

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“…3d). These results are in agreement with a previous study in gastric and breast cancer cell lines [8,12], showing that silencing FAT4 expression increased invasion and migration of MDA-MB-436 and BT-549 breast Fig. 3 Functional role of FAT4 on cell proliferation, colony formation, and invasive ability.…”

Section: Discussionsupporting

confidence: 93%

“…FAT tumor suppressor homolog 4 (FAT4), is a member of the FAT family that consists of (FAT1-4) and encodes a single transmembrane protein containing 32-34 extracellular cadherin repeats, a transmembrane domain and a cytoplasmic domain [7]. FAT4 was identified as a tumor suppressor in mouse mammary epithelial cell line and triple-negative breast cancer [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…There is increasing evidence of a possible relation between the FAT4 downregulation and the pathogenesis of several malignancies, including breast, colorectal, and gastric cancers [8,12,13]. Also, previous mutational screening studies revealed missense and nonsense mutations of FAT4 in hepatocellular (10%) [14], pancreatic (8%) [15], head-and-neck squamous cell cancers (6%) [16], endometrioid, and mucinous primary ovarian tumors (15%) [17].…”

Section: Introductionmentioning

confidence: 99%

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FAT4 silencing promotes epithelial-to-mesenchymal transition and invasion via regulation of YAP and β-catenin activity in ovarian cancer

et al. 2020

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Background: The adhesion molecule, FAT4, has a tumor suppressor function with a critical role in the epithelial-tomesenchymal-transition (EMT) and anti-malignant growth in several cancers. No study has investigated yet its role in epithelial ovarian cancer (EOC) progression. In the present study, we examined the role of FAT4 in proliferation and metastasis, and its mechanisms of interaction in these processes. Methods: We have performed cell viability, colony formation, and invasion assays in ovarian cancer cells treated with siRNA to knockdown FAT4 gene expression. The regulatory effects of FAT4 on proteins involved in apoptotic, Wnt, Hippo, and retinoblastoma signaling pathways were evaluated by Western blotting following FAT4 repression. Also, 426 ovarian tumor samples and 88 non-tumor samples from the Gene Expression Profiling Interactive Analysis (GEPIA) database were analyzed for the expression of FAT4. Pearson's correlation was performed to determine the correlation between FAT4 and the E2F5, cyclin D1, cdk4, and caspase 9 expressions. Results: Lower expression of FAT4 was observed in ovarian cancer cell lines and human samples as compared to non-malignant tissues. This down-regulation seems to enhance cell viability, invasion, and colony formation. Silencing FAT4 resulted in the upregulation of E2F5, vimentin, YAP, β-catenin, cyclin D1, cdk4, and Bcl2, and in the downregulation of GSK-3-β, and caspase 9 when compared to control. Furthermore, regulatory effects of FAT4 on the EMT and aggressive phenotype seem to occur through Hippo, Wnt, and cell cycle pathways. Conclusion: FAT4 downregulation promotes increased growth and invasion through the activation of Hippo and Wnt-β-catenin pathways.

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“…The roles of TUSC3 in cancer progression showed context-dependent manner in several solid tumors. TUSC3 was initially identified as a homozygous deleted gene in metastasized prostate cancer patients and its deficiency upregulated cancer progression and tumorigenesis in ovarian, prostate, glioblastoma and pancreatic cancers 20 – 24 . However, it has been also reported that TUSC3 was associated with genetic amplification or enhanced cancer progression in head and neck cancer and colorectal cancer 20 , 25 , 26 .…”

Section: Introductionmentioning

confidence: 99%

miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC

et al. 2018

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Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.

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FAT4 functions as a tumor suppressor in triple-negative breast cancer

Cited by 28 publications

References 18 publications

Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort

Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort

FAT4 silencing promotes epithelial-to-mesenchymal transition and invasion via regulation of YAP and β-catenin activity in ovarian cancer

miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC

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