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. 2025 Jan 22;52(1):150.
doi: 10.1007/s11033-025-10271-2.

Suppression of chemically induced mammary cancer by early-life oral administration of cholera toxin in mice is associated with aberrant regulation of Bmp and Notch signaling pathways

Dimitrios G Argyris  1   2   3 , Maria P Markaki  1 , Hara Afaloniati  1 , George S Karagiannis  2   3 , Theofilos Poutahidis  4 , Katerina Angelopoulou  5
Affiliations

Suppression of chemically induced mammary cancer by early-life oral administration of cholera toxin in mice is associated with aberrant regulation of Bmp and Notch signaling pathways

Dimitrios G Argyris et al. Mol Biol Rep. .

Abstract

Background: Lately, significant attention has been drawn towards the potential efficacy of cholera toxin (CT)-an exotoxin produced by the small intestine pathogenic bacterium Vibrio cholera-in modulating cancer-promoting events. In a recent study, we demonstrated that early-life oral administration of non-pathogenic doses of CT in mice suppressed chemically-induced carcinogenesis in tissues distantly located from the gut. In the mammary gland, CT pretreatment was shown to reduce tumor multiplicity, increase apoptosis and alter the expression of several cancer-related molecules. In the present work we investigated the protumorigenic mammary microenvironment for possible associations between early life CT administration and the expression of key components of the Bmp and Notch signaling pathways.

Methods and results: Total RNA from mammary tissue samples were retrieved from a recent experiment where FVB/N female mice were preconditioned with CT and later treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA). Real-time PCR was used for relative quantification of gene expression. Our results revealed that CT anti-tumor effects significantly correlated with deregulation of crucial BMP pathway elements, with downregulation of Bmp7 ligand and upregulation of inhibitory Smad6 being the most prominent alterations observed. Concerning Notch signaling pathway, significantly elevated gene expression levels in the CT-treated DMBA mice, as compared to their non-treated counterparts, were also identified at the ligand-receptor level.

Conclusions: These findings suggest that CT tumor protective effects in the mammary gland are associated with discerning deregulation of components of both Bmp and Notch signaling pathways and provide insights into the mechanisms underlying CT's anti-cancer outcome.

Keywords: 7,12-dimethylbenzanthracene (DMBA); Bone morphogenetic proteins (Bmp); Cholera toxin (CT); Mammary cancer; Notch.

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Conflict of interest statement

Declarations. Competing interests: The authors have no competing interests to declare that are relevant to the content of this article. Ethical approval: Total RNA samples used in the present study were retrieved from an earlier experiment, which was approved by the Faculty of Veterinary Medicine, Aristotle University of Thessaloniki and licensed by the competent National Veterinary Administration authorities (License No: 122149/765/12.04.18).

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