We have previously shown that T2, an N4-aryl-substituted thiosemicarbazone, exerts cytotoxic and anti-invasive effects in triple-negative breast cancer (TNBC) and increases expression of the metastasis suppressor N-myc downstream-regulated gene 1 (NDRG1). Given the role of NDRG1 in regulating epithelial mesenchymal transition (EMT) and WNT/{beta}-catenin signaling, we investigated the contribution of this pathway to the anti-invasive activity of T2. The effects of T2 on WNT/{beta}-catenin signaling and associated microRNAs (miR-182-5p and miR-200c) were evaluated in 4T1 cells. In vivo activity was assessed using a fully immunocompetent intraductal 4T1 mouse model that recapitulates the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Tumor progression, invasion, NDRG1 expression, and WNT/{beta}-catenin pathway components were analyzed. T2 reduced WNT/{beta}-catenin signaling and modulated the expression of miR-182-5p and miR-200c in vitro. In the MIND model, T2 decreased the frequency of invasive lesions and reduced {beta}-catenin, ZEB1, and c-Myc expression while increasing NDRG1 levels. {beta}-catenin localization differed between lesion types, showing predominantly membrane-associated staining in DCIS lesions and a diffuse cytoplasmic distribution in invasive foci. These findings identify WNT/{beta}-catenin signaling and NDRG1-associated pathways as potential mediators of the anti-invasive effects of T2 in TNBC. The reduction in invasive progression observed in the MIND model supports further investigation of this compound in preclinical models of TNBC.
Solimo, A. M., Sciacca, M., Cascardo, F., Finkielsztein, L., Eijan, A. M., Lodillinsky, C., Callero, M. A.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 12
- Comments 0