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

Shu Chen ^1,2, Xi Zhang ^1,3, Basappa Basappa ⁴

¹Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China.
²Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, PR China.
³Shenzhen Bay Laboratory, Shenzhen, Guangdong, PR China.
⁴Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, Karnataka, India.
⁵Department of Oncology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, PR China.
⁶Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, PR China.
⁷Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China. vijay.pandey@sz.tsinghua.edu.cn.
⁸Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, PR China. vijay.pandey@sz.tsinghua.edu.cn.
⁹Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China. pelobie@sz.tsinghua.edu.cn.
¹⁰Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, PR China. pelobie@sz.tsinghua.edu.cn.
¹¹Shenzhen Bay Laboratory, Shenzhen, Guangdong, PR China. pelobie@sz.tsinghua.edu.cn.

⁰Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China.

Communications Medicine +

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February 21, 2025

View abstract on PubMed

Summary

Trefoil factor 3 (TFF3) drives estrogen receptor-positive mammary carcinoma dormancy. Combining a TFF3 inhibitor with CDK4/6 inhibitors shows promise in treating this challenging condition.

Area Of Science

Oncology
Molecular Biology
Pharmacology

Background

Tumor dormancy in estrogen receptor-positive mammary carcinoma (ER+MC) presents a significant clinical challenge, leading to treatment resistance, metastasis, and mortality.
Understanding the mechanisms of ER+MC dormancy is crucial for developing effective therapeutic strategies.

Purpose Of The Study

To generate preclinical models of anti-estrogen-induced ER+MC dormancy.
To identify key molecular drivers of dormancy and evaluate combination therapies.

Main Methods

Generated in vivo preclinical models mimicking clinical anti-estrogen-induced ER+MC dormancy.
Investigated dormancy mechanisms and tested combination treatments in vitro, ex vivo, and in vivo.
Utilized molecular profiling and drug screening assays.

Main Results

Identified Trefoil factor 3 (TFF3) as a prognostic indicator and epigenetic driver of ER+MC dormancy.
Demonstrated that TFF3 inhibition combined with CDK4/6 inhibitors synergistically reduces cell proliferation and induces apoptosis.
Showed that this combination therapy impedes metastatic outgrowth and improves survival in dormancy models.

Conclusions

Trefoil factor 3 (TFF3) is a key driver of anti-estrogen-induced ER+MC dormancy.
Combined inhibition of TFF3 and CDK4/6 offers a potential therapeutic approach to overcome dormancy-related clinical challenges in ER+MC.