Expression of Lymphoid Enhancer-Binding Factor 1 in Cancer-Associated Fibroblasts Mediates Tumor Growth and Transdifferentiation Toward Squamous Cell Carcinoma in Human Breast Cancer

Overview

Journal Cancer Med

Date 2025 Jan 31

PMID 39887653

Authors

Hiroya Okazaki

Yoshihiro Mezawa

Yang Shi

Mizuki Sakimoto

Zixu Wang

Akane Ishizuka

Kazunari Yamashita

Asahi Satoh

Yu Koyama

Yuki Fukumura

Kazunori Kajino

Atsushi Takano

Tomoyuki Yokose

Toshinari Yamashita

Yohei Miyagi

Yataro Daigo

Akira Katakura

Takehiro Yasukawa

Akira Orimo

Affiliations

Soon will be listed here.

Abstract

Background: Cancer-associated fibroblasts (CAFs) play a significant role in human breast cancer as a major stromal component. While their role in promoting cancer proliferation and malignancy through interaction with cancer cells in the tumor microenvironment is known, the exact mechanisms behind this interaction are not fully understood.

Results: Our study reveals that lymphoid enhancer-binding factor 1 (LEF1), a central transcription factor for Wnt/β-catenin signaling, is expressed in experimentally generated tumor-promoting CAFs (exp-CAFs) as well as in CAFs from breast cancer patients, particularly those with a poor prognosis. Notably, LEF1-expressing CAFs are prevalent in the stroma of squamous cell carcinoma (SCC), an aggressive metaplastic breast cancer subtype with a limited understanding of its development. To investigate the functional importance of LEF1 expression in CAFs, we depleted LEF1 in the exp-CAFs and subcutaneously implanted them along with breast ductal carcinoma MCF10DCIS.com cells into immunodeficient mice. Depleting LEF1 resulted in reduced xenograft tumor growth, accompanied by decreased cancer-cell proliferation and angiogenesis in the tumors. Additionally, we observed a significant reduction in the expression of SCC markers p40 (ΔNp63) and cytokeratin 5/6 in the xenograft tumors when LEF1 was depleted in the exp-CAFs. Furthermore, we identified 13 genes, none of which are established downstream genes of the Wnt/β-catenin pathway, that exhibit expression patterns similar to LFE1 in our cultured fibroblasts.

Conclusion: In summary, our findings suggest that LEF1 expression contributes to the tumor-promoting abilities of breast CAFs and that LEF1-expressing CAFs may drive transdifferentiation toward SCC, possibly through a pathway independent of the canonical Wnt/β-catenin signaling.

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