Work

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

Year: 2025

Type: article

Abstract: 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. 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. 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. 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. Estrogen receptor positive mammary carcinoma is a common type of breast cancer. It is difficult to cure as the cancer cells stop dividing but survive upon treatment leaving the cancer dormant. It then recurs years or even decades later. To address this challenge, mouse models of dormant estrogen receptor positive mammary carcinoma were developed. It was observed that a protein, TFF3, reduced the chance of survival. A combination treatment was found to be able to treat the dormant cancer in the mice models. The combination approach uses an experimental drug to inhibit TFF3 with clinically used drugs. These results suggest a possible treatment for people with this type of cancer. Chen et al. generate mimicking dormant clinical anti-estrogen-induced estrogen receptor positive mammary carcinoma (ER+MC) models. TFF3 is identified as a prognostic indicator and epigenetically regulated oncogenic driver of anti-estrogen-induced dormancy in ER+MC with combined inhibition of TFF3 and CDK4/6 exhibiting potential to ameliorate outcomes in anti-estrogen-induced ER+MC.

Source: Communications Medicine

DOI: 10.1038/s43856-024-00710-9

Authors: Shu Chen, Xi Zhang, Basappa Basappa, Tao Zhu, Vijay Pandey, Peter E. Lobie