TFF3 facilitates dormancy of anti-estrogen treated ER+ mammary carcinoma

Chen,, Shu and Basappa,, Basappa and Zhu,, Tao and Pandey, Vijay (2025) TFF3 facilitates dormancy of anti-estrogen treated ER+ mammary carcinoma. Communications Medicine, 5 (1). pp. 1-17. ISSN 2730664X

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Abstract

Background: Tumor dormancy is a substantial clinical obstacle in treatment of estrogen receptor positive mammary carcinoma (ER+MC), contributing to drug resistance, metastatic outgrowth, relapse, and consequent mortality. Methods: Preclinical models mimicking clinical anti-estrogen-induced ER+MC dormancy were generated in vivo. Function and a mechanism-based combination treatment were determined in the generated dormancy-like models in vitro, ex vivo, and in vivo. Results: The dormancy models display molecular features of dormancy and tumor mass and cellular dormancy with associated clinical dormancy behavior. Both serum and cancer tissue expression of Trefoil factor 3 (TFF3) are identified as prognostic indicators of dormant ER+MC with TFF3 functioning as an epigenetically regulated driver of dormancy-associated behaviors. BCL2-dependent pro-survival functions of TFF3 coupled with enhanced attributes of stemness designates TFF3 as an actionable target. Moreover, combination screening of a TFF3 small-molecule-inhibitor (AMPC) with compounds used clinically to treat anti-estrogen-resistant ER+MC identifies strong synergism between AMPC and CDK4/6 inhibitors in the dormancy-like models. The combination results in concomitant suppression of CCND1 expression and CDK4/6 kinase activity to decrease RB phosphorylation, with reduced BCL2 expression, leading to both ER + MC cell cycle arrest and apoptosis. The combined TFF3-CDK4/6 inhibition impedes metastatic outgrowth and ameliorates host animal survival in the dormancy-like models, producing a complete response in a percentage of animals. Conclusions: Hence, in vivo models of anti-estrogen induced dormancy of ER+MC generated herein, identify TFF3 as a driver of this process. The combined inhibition of TFF3 and CDK4/6 may potentially alleviate the clinical challenges posed by anti-estrogen-induced dormancy in ER+MC. © The Author(s) 2025.

Item Type:	Article
Uncontrolled Keywords:	Tumor dormancy, Metastatic outgrowth
Subjects:	C Chemical Science > Chemistry
Divisions:	Department of > Chemistry
Depositing User:	Vasantha library uom
Date Deposited:	21 Nov 2025 10:51
Last Modified:	21 Nov 2025 10:51
URI:	http://eprints.uni-mysore.ac.in/id/eprint/17985

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