Loss of FAT1 drives cyclophosphamide resistance in breast cancer via the Wnt/β-Catenin pathway
Drug resistance remains a major obstacle to successful chemotherapy, leading to treatment failure and tumor recurrence. Recent studies indicate that mutations in FAT Atypical Cadherin 1 (<i>FAT1</i>) contribute to drug resistance in cancer cells. However, the precise role and underlying mechanisms of <i>FAT1</i> in breast cancer (BC) remain insufficiently explored. Here, we conducted a comprehensive genomic and transcriptomic analysis, identifying <i>FAT1</i> as a crucial tumor suppressor gene in BC. Our study demonstrates that genomic alterations in <i>FAT1</i> are associated with the Wnt/β-catenin pathway activation. We further show that <i>FAT1</i> loss induces cyclophosphamide (CTX) resistance and leads to the upregulation of the Wnt signaling cascade, accompanied by the accumulation of CTNNB1 transcription factors. Notably, combination therapy effectively alleviates drug resistance by suppressing the Wnt pathway. These findings highlight the critical role of <i>FAT1</i> loss in mediating CTX resistance in BC and provide insights into potential therapeutic strategies targeting the Wnt pathway.
Authors
- Heming Xu
- Xuan Tang (ORCID: https://orcid.org/0000-0002-6074-9633)
- Shasha Zhao (ORCID: https://orcid.org/0000-0003-4886-3182)
- Lijing Zhong (ORCID: https://orcid.org/0000-0001-7567-8359)
- Gengming Niu (ORCID: https://orcid.org/0000-0001-6523-1019)
- Dongxi Xiang (ORCID: https://orcid.org/0000-0001-9192-6295)
- Zheng Chen (ORCID: https://orcid.org/0000-0003-0961-8758)
- Jian Zhang (ORCID: https://orcid.org/0000-0001-9877-1601)
- Jingyuan Wen (ORCID: https://orcid.org/0000-0001-7833-5546)
- Li-Yi Zhang (ORCID: https://orcid.org/0000-0002-9731-4385)
- Dongyan Cao (ORCID: https://orcid.org/0000-0002-7260-2495)
- Yuxuan Xu (ORCID: https://orcid.org/0000-0003-2804-6695)
- Paul W. R. Harris (ORCID: https://orcid.org/0000-0002-2579-4543)
- Aina He
- Guiying Wei (ORCID: https://orcid.org/0000-0002-9440-9928)
- Xiao Liu (ORCID: https://orcid.org/0000-0002-8029-0217)
Institutions
- Guangxi Medical University (CN)
- Renji Hospital (CN)
- First Affiliated Hospital of Xiamen University (CN)
- Jiaxing University (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shanghai Cancer Institute (CN)
- Maurice Wilkins Centre (NZ)
- First Hospital of Jiaxing (CN)
- Shanghai Sixth People's Hospital (CN)
Publication Details
- Journal
- International Journal of Biological Sciences
- Published
- 2025-12-06
- DOI
- https://doi.org/10.7150/ijbs.117161
- Primary Topic
- Wnt/β-catenin signaling in development and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Guangxi Medical University