TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2

• Published in: eLife Vol. 6
• Main Authors: Ku, Amy T, Shaver, Timothy M, Rao, Ajay S, Howard, Jeffrey M, Rodriguez, Christine N, Miao, Qi, Garcia, Gloria, Le, Diep, Yang, Diane, Borowiak, Malgorzata, Cohen, Daniel N, Chitsazzadeh, Vida, Diwan, Abdul H, Tsai, Kenneth Y, Nguyen, Hoang
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 03.05.2017; eLife Sciences Publications, Ltd
• Subjects: Animals; beta Catenin - metabolism; Biology; Breast cancer; Cancer Biology; Carcinogenesis; Carcinoma, Squamous Cell - physiopathology; Cell Biology; Cell migration; Defects; Disease Models, Animal; Gene expression; Gene Expression Profiling; Genes; Heterografts; Humans; Lipocalin-2 - metabolism; Medical research; Medicine; Mice; oncogene-induced senescence; Pathology; Rodents; Senescence; Skin; Skin cancer; Skin Neoplasms - physiopathology; skin squamous cell carcinoma; Software; Squamous cell carcinoma; Stem cells; TCF7L1; Transcription Factor 7-Like 1 Protein - metabolism; Transcription factors; Tumorigenesis; Tumors; Xenografts; β-Catenin; United States > US; mouse; TCF7L1; cell biology; skin squamous cell carcinoma; cell migration; cancer biology; human; oncogene-induced senescence
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.23242

The transcription factor is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with β-catenin. Through transcriptome profiling and combined gain- and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity.