Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma

Chuyu, H. and Xuejuan, W. and Yi-Shiou, C. and Basappa, B. and Pandey, V. and Lobie, P. E. (2025) Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma. Cell Death and Disease, 16 (1). pp. 1-19. ISSN 20414889

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Abstract

The interaction between HER2 and ERα signaling pathways contributes to resistance to anti-estrogen and HER2-targeted therapies, presenting substantial treatment challenges in ER-positive (ER+) HER2-positive (HER2+) mammary carcinoma (MC). Trefoil Factor-3 (TFF3) has been reported to mediate resistance to both anti-estrogen and anti-HER2 targeted therapies in ER+ and ER+HER2+ MC, respectively. Herein, the function and mechanism of TFF3 in ER+HER2+ MC were delineated; and novel combinatorial therapeutic strategies were identified. Elevated expression of TFF3 promoted the oncogenicity of ER+HER2+ MC cells, including enhanced cell proliferation, survival, anchorage-independent growth, 3D growth, cancer stem cell-like (CSC-like) phenotype, migration, invasion, and xenograft growth. Targeting TFF3 with an interfering RNA plasmid or a small-molecule inhibitor (AMPC) inhibited these oncogenic characteristics, highlighting the therapeutic potential of targeting TFF3 in ER+HER2+ MC. Furthermore, a high-throughput combinatorial anti-cancer compound library screening revealed that AMPC preferentially synergized with receptor tyrosine kinase c-MET inhibitors (c-METis) to reduce cell survival and the CSC-like phenotype. The combination of AMPC and c-METis also synergistically suppressed the in vivo growth of ER+HER2+ MC cell-derived xenografts and abrogated lung metastasis. Mechanistically, TFF3 was observed to activate c-MET signaling through a positive-feedback loop to enhance the CSC-like phenotype of ER+HER2+ MC. Therefore, proof of concept is provided herein that antagonizing of TFF3 is a promising therapeutic strategy in combination with c-MET inhibition for the treatment of ER+HER2+ MC.

Item Type:	Article
Uncontrolled Keywords:	Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Synergism; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplastic Stem Cells; Phenotype; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Receptor, ErbB-2; Receptors, Estrogen; Signal Transduction; Trefoil Factor-3; Xenograft Model Antitumor Assays
Subjects:	C Chemical Science > Chemistry
Divisions:	Department of > Chemistry
Depositing User:	Vasantha library uom
Date Deposited:	21 Nov 2025 11:37
Last Modified:	21 Nov 2025 11:37
URI:	http://eprints.uni-mysore.ac.in/id/eprint/17987

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