Thiosemicarbazone T2 suppresses WNT/β-catenin signaling and limits progression to invasive disease in a mouse intraductal model of triple-negative breast cancer
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T2, an N4-aryl-substituted thiosemicarbazone, has previously been shown to exert cytotoxic and anti-invasive effects in triple-negative breast cancer (TNBC) and to increase 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/β-catenin signaling, we investigated the contribution of this pathway to the anti-invasive activity of T2.
The effects of T2 on WNT/β-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/β-catenin pathway components were analyzed.
T2 reduced WNT/β-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 β-catenin, ZEB1, and c-Myc expression while increasing NDRG1 levels. β-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/β-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.
