Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

Abstract

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, fibronection-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.

Cadmium stimulates metastasis-associated phenotype in triple-negative breast cancer cells through integrin and β-catenin signaling

“…In triple-negative breast cancer cells, the integrin-dependent metastasis-associated phenotypes are accompanied by the upregulation of Wnt/β-catenin pathway (De et al, 2016). The present study examined whether Cd could activate Wnt/β-catenin pathway without engaging integrins in the MDA-MB-231 cells.…”

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression

“…Altered β-catenin expression/subcellular localization also plays a major role in EMT process in various malignancies including PrCa (6). Studies have suggested involvement of β‐catenin in the development, progression and therapy resistance of advanced PrCa (3).…”

MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development

“…For example, the AR_CTNNB1 PPI essentiality rank percentile was very high in a number of cell lines including COLO704 ovarian (99%ile), and BT20 (98%ile) and MDA-MB-453 (97%ile) triple-negative breast cancer cell lines. Both Wnt [38] and androgen signaling [39] have been shown to be important in subsets of ovarian and triple-negative breast cancers [40–42]. Another example of signaling crosstalk identified by this analysis is that of YAP1_CTNNB1 interactions in L363 myeloma cells (94%ile), CADO-ES1 Ewing’s sarcoma cells (96%ile), and A204 rhabdomyosarcoma cells (96%ile).…”