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bioRxiv · 10.64898/2026.06.05.730419

Thiosemicarbazone T2 suppresses WNT/β-catenin signaling and limits progression to invasive disease in a mouse intraductal model of triple-negative breast cancer

Solimo, A. M.·Sciacca, M.·Cascardo, F.·Finkielsztein, L.·Eijan, A. M.·Lodillinsky, C.·Callero, M. A.
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Abstract

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/{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.

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Solimo, A. M., Sciacca, M., Cascardo, F., Finkielsztein, L., Eijan, A. M., Lodillinsky, C., Callero, M. A.. 2026-06-09. Thiosemicarbazone T2 suppresses WNT/β-catenin signaling and limits progression to invasive disease in a mouse intraductal model of triple-negative breast cancer. https://doi.org/10.64898/2026.06.05.730419

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