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Independent Negative Prognostic Role of TCF1 Expression within the Wnt/?-Catenin Signaling Pathway in Primary Breast Cancer Patients.

ABSTRACT: The Wnt pathway is involved in the progression of breast cancer (BC). We aimed to evaluate the expression of some components of the Wnt pathway (?-catenin, FZD4 (frizzled receptor 4), LRP5 (low-density lipoprotein receptor-related protein 5), LRP6, and TCF1 (T-cell factor 1)) to detect potential associations with NHERF1 (Na+/H+ exchanger regulatory factor 1) protein. Besides, we assessed their impact on patients' clinical outcome. We evaluated 220 primary BC samples by immunohistochemistry (IHC) and protein localization by immunofluorescence. We found a significant correlation between NHERF1 and FZD4, LRP5, LRP6, and TCF1. Univariate analysis showed that the overexpression of ?-catenin (p < 0.0001), FZD4 (p = 0.0001), LRP5, LRP6, and TCF1 (p < 0.0001 respectively) was related to poor disease-free survival (DFS). A Kaplan-Meier analysis confirmed univariate data and showed a poor DFS for cNHERF1+/FZD4+ (p = 0.0007), cNHERF1+/LRP5+ (p = 0.0002), cNHERF1+/LRP6+ (p < 0.0001), and cNHERF1+/TCF1+ phenotypes (p = 0.0034). In multivariate analysis, the expression of TCF1 and ?-catenin was an independent prognostic variable of worse DFS (p = 0.009 and p = 0.027, respectively). In conclusion, we found that the overexpression of ?-catenin, FZD4, LRP5, LRP6, and TCF1 was associated with poor prognosis. Furthermore, we first identified TCF1 as an independent prognostic factor of poor outcome, indicating it as a new potential biomarker for the management of BC patients. Also, the expression of Wnt pathway proteins, both alone and in association with NHERF1, suggests original associations of biological significance for new studies.

SUBMITTER: Saponaro C

PROVIDER: S-EPMC6678184 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients.

Saponaro Concetta C Scarpi Emanuela E Zito Francesco Alfredo FA Giotta Francesco F Silvestris Nicola N Mangia Anita A

Cancers 20190722 7

The Wnt pathway is involved in the progression of breast cancer (BC). We aimed to evaluate the expression of some components of the Wnt pathway (β-catenin, FZD4 (frizzled receptor 4), LRP5 (low-density lipoprotein receptor-related protein 5), LRP6, and TCF1 (T-cell factor 1)) to detect potential associations with NHERF1 (Na+/H+ exchanger regulatory factor 1) protein. Besides, we assessed their impact on patients' clinical outcome. We evaluated 220 primary BC samples by immunohistochemistry (IHC) ...[more]

PMID: 31336689

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Project description:Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronectin-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.

Project description:The acquisition of integrin-directed metastasis-associated (ID-MA) phenotypes by Triple-Negative Breast Cancer (TNBC) cells is caused by an upregulation of the Wnt-beta-catenin pathway (WP). We reported that WP is one of the salient genetic features of TNBC. RAC-GTPases, small G-proteins which transduce signals from cell surface proteins including integrins, have been implicated in tumorigenesis and metastasis by their role in essential cellular functions like motility. The collective percentage of alteration(s) in RAC1 in ER+ve BC was lower as compared to ER-ve BC (35% vs 57%) (brca/tcga/pub2015). High expression of RAC1 was associated with poor outcome for RFS with HR=1.48 [CI: 1.15-1.9] p=0.0019 in the Hungarian ER-veBC cohort. Here we examined how WP signals are transduced via RAC1 in the context of ID-MA phenotypes in TNBC. Using pharmacological agents (sulindac sulfide), genetic tools (beta-catenin siRNA), WP modulators (Wnt-C59, XAV939), RAC1 inhibitors (NSC23766, W56) and WP stimulations (LWnt3ACM, Wnt3A recombinant) in a panel of 6-7 TNBC cell lines, we studied fibronectin-directed (1) migration, (2) matrigel invasion, (3) RAC1 and Cdc42 activation, (4) actin dynamics (confocal microscopy) and (5) podia-parameters. An attenuation of WP, which (a) decreased cellular levels of beta-catenin, as well as its nuclear active-form, (b) decreased fibronectin-induced migration, (c) decreased invasion, (d) altered actin dynamics and (e) decreased podia-parameters was successful in blocking fibronectin-mediated RAC1/Cdc42 activity. Both Wnt-antagonists and RAC1 inhibitors blocked fibronectin-induced RAC1 activation and inhibited the fibronectin-induced ID-MA phenotypes following specific WP stimulation by LWnt3ACM as well as Wnt3A recombinant protein. To test a direct involvement of RAC1-activation in WP-mediated ID-MA phenotypes, we stimulated brain-metastasis specific MDA-MB231BR cells with LWnt3ACM. LWnt3ACM-stimulated fibronectin-directed migration was blocked by RAC1 inhibition in MDA-MB231BR cells. In the light of our previous report that WP upregulation causes ID-MA phenotypes in TNBC tumor cells, here we provide the first mechanism based evidence to demonstrate that WP upregulation signals ID-MA tumor cell phenotypes in a RAC1-GTPase dependent manner involving exchange-factors like TIAM1 and VAV2. Our study demonstrates for the first time that beta-catenin-RAC1 cascade signals integrin-directed metastasis-associated tumor cell phenotypes in TNBC.

Dataset Information

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/?-Catenin Signaling Pathway in Primary Breast Cancer Patients.

Publications

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients.

Similar Datasets

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