# Low tumoral Trefoil Factor 1 expression relates to aggressive tumor features and poor survival in young women with breast cancer

## TL;DR

Low levels of Trefoil Factor 1 in breast cancer tumors are linked to aggressive cancer features and worse survival in young women.

## Contribution

This study identifies Trefoil Factor 1 as a potential biomarker for aggressive breast cancer in young patients.

## Key findings

- Low TFF1 expression correlates with younger age, aggressive tumor features, and poor survival in young breast cancer patients.
- TFF1-low tumors show stem-like traits, immune checkpoint upregulation, and higher proliferation scores.
- High TFF1 in lymph node metastases predicts worse survival in patients under 40.

## Abstract

In young breast cancer (BC) patients, there is a need for additional biomarkers beyond those currently available. Trefoil Factor 1 (TFF1) is an estrogen-regulated protein with proposed prognostic relevance in BC. We assessed TFF1 protein expression by immunohistochemistry (IHC) in biopsies from patients with primary breast cancer diagnosed before age 50 and their paired axillary lymph node (LN) metastases within our in-house Bergen Young BC Cohort (n = 319). In addition, TFF1 mRNA levels and associated gene expression patterns were analyzed using publicly available datasets, including the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 939) and the Cancer Cell Line Encyclopedia (n = 47). Our aim was to investigate how TFF1 expression in primary tumors (PT) and paired LN metastases relates to age at diagnosis, clinico-pathological features, and disease-specific survival, and to explore TFF1-associated gene expression profiles. Low TFF1 protein and mRNA expression in PTs was associated with younger age, aggressive clinico-pathologic features, and poorer survival. Additionally, TFF1 mRNA expression was a strong predictor of the basal-like subtype, and TFF1-low tumors exhibited stem-like characteristics, upregulation of immune checkpoints, and higher proliferation scores. In LN metastases, low TFF1 protein expression was associated with aggressive tumor features. Notably, high TFF1 protein expression in LN metastases predicted poorer survival in patients under 40 years. Our results indicate that low BC TFF1 expression is associated with younger age and aggressive tumor features, on top of serving as a predictor of the basal-like subtype. High TFF1 protein expression in LN metastases may carry prognostic significance for younger patients.

The online version contains supplementary material available at 10.1038/s41598-026-36341-4.