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Updated: Jun 27, 2026
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Published on: July 3, 2025
Identification of Fat4 as a candidate tumor suppressor gene in breast cancers
Chao Qi1, Yiwei Tony Zhu, Liping Hu
1Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA.
Abstract:
Fat, a candidate tumor suppressor in Drosophila, is a component of Hippo signaling pathway involved in controlling organ size. We found that a approximately 3 Mbp deletion in mouse chromosome 3 caused tumorigenesis of a non-tumorigenic mammary epithelial cell line. The expression of Fat4 gene, one member of the Fat family, in the deleted region was inactivated, which resulted from promoter methylation of another Fat4 allele following the deletion of one Fat4 allele. Re-expression of Fat4 in Fat4-deficient tumor cells suppressed the tumorigenecity whereas suppression of Fat4 expression in the non-tumorigenic mammary epithelial cell line induced tumorigenesis. We also found that Fat4 expression was lost in a large fraction of human breast tumor cell lines and primary tumors. Loss of Fat4 expression in breast tumors was associated with human Fat4 promoter methylation. Together, these findings suggest that Fat4 is a strong candidate for a breast tumor suppressor gene.
Insights
Fat4 acts as a tumor suppressor gene in breast cancer. Loss of Fat4 expression, often due to promoter methylation, promotes tumor development, while its re-expression inhibits it.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Fat proteins are involved in the Hippo signaling pathway, regulating organ size.
- The role of Fat family genes in mammalian tumorigenesis is not fully understood.
Purpose of the Study:
- To investigate the role of the Fat4 gene in mammary epithelial cell tumorigenesis.
- To determine if Fat4 functions as a tumor suppressor in breast cancer.
Main Methods:
- Induced a deletion in mouse chromosome 3 in mammary epithelial cells.
- Analyzed Fat4 gene expression and promoter methylation.
- Assessed the effect of Fat4 re-expression or suppression on tumorigenicity.
- Examined Fat4 expression and methylation in human breast tumor samples.
Main Results:
- A deletion on mouse chromosome 3 led to mammary epithelial cell tumorigenesis.
- Loss of Fat4 gene expression, caused by deletion and subsequent promoter methylation, was observed.
- Re-expression of Fat4 suppressed tumor cell growth, while its suppression induced tumorigenesis.
- Fat4 expression was frequently lost in human breast tumors, associated with promoter methylation.
Conclusions:
- Fat4 functions as a tumor suppressor gene in breast cancer.
- Loss of Fat4 expression, through genetic deletion and promoter methylation, contributes to breast tumorigenesis.
- Fat4 is a potential therapeutic target for breast cancer treatment.
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