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Updated: Jan 11, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Family with sequence similarity 114 member A1 orchestrates immune evasion in triple-negative breast cancer
Wenhao Zhang1, Yanzhi Gai2, Mengxue Qiao1
1Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Abstract:
Immune checkpoint blockade (ICB) therapy, which has revolutionized cancer treatment, has been approved for the treatment of triple-negative breast cancer (TNBC). Unfortunately, most patients with TNBC are either not eligible for treatment or exhibit resistance, resulting in limited overall survival benefits. There is an urgent need to elucidate the mechanisms of resistance and enhance therapeutic efficacy. Here, via CRISPR activation (CRISPRa) screening, we identified family with sequence similarity 114 member A1 (FAM114A1) as a key mediator of immune evasion and ICB resistance in TNBC. Mechanistically, FAM114A1 binds p85α to disrupt the p85α/p110α protein complex, thus activating the PI3K/AKT pathway and simultaneously preventing condensate formation of E2F Transcription Factor 4 (E2F4) to promote E2F4-driven Metadherin (MTDH) transcription. Upregulation of these FAM114A1-mediated pathways suppresses tumor antigen presentation and consequently attenuates antitumor immunity in TNBC. Moreover, targeting FAM114A1 improves the therapeutic effectiveness of anti-PD-1 therapy in mouse models, and a FAM114A1-based signature shows strong predictive performance for identifying patients with TNBC who may benefit from ICB. Collectively, our findings not only reveal that FAM114A1 is an immune evasion driver but also highlight it as a promising biomarker and therapeutic target. Our study provides new insights into TNBC immune evasion and outlines a potential avenue to improve the effectiveness of ICB.
Insights
Researchers identified Family with sequence similarity 114 member A1 (FAM114A1) as a key driver of immune evasion and resistance to immune checkpoint blockade (ICB) therapy in triple-negative breast cancer (TNBC). Targeting FAM114A1 shows promise for improving TNBC treatment efficacy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint blockade (ICB) therapy offers significant advancements in cancer treatment, including for triple-negative breast cancer (TNBC).
- However, a substantial proportion of TNBC patients exhibit resistance or are ineligible for ICB, necessitating research into underlying mechanisms and improved therapeutic strategies.
Purpose of the Study:
- To identify key mediators of immune evasion and ICB resistance in TNBC.
- To elucidate the molecular mechanisms by which these mediators contribute to therapeutic resistance.
- To evaluate FAM114A1 as a potential therapeutic target and predictive biomarker for ICB in TNBC.
Main Methods:
- CRISPR activation (CRISPRa) screening was employed to identify genes involved in immune evasion and ICB resistance.
- Molecular mechanisms involving FAM114A1, p85α, PI3K/AKT pathway, E2F4, and MTDH were investigated.
- The efficacy of targeting FAM114A1 in combination with anti-PD-1 therapy was assessed in mouse models.
- A FAM114A1-based signature was developed to predict patient response to ICB.
Main Results:
- Family with sequence similarity 114 member A1 (FAM114A1) was identified as a critical mediator of immune evasion and ICB resistance in TNBC.
- FAM114A1 activates the PI3K/AKT pathway and promotes MTDH transcription by disrupting the p85α/p110α complex and preventing E2F4 condensate formation.
- These FAM114A1-driven pathways suppress tumor antigen presentation, leading to reduced antitumor immunity.
- Targeting FAM114A1 enhanced the efficacy of anti-PD-1 therapy in preclinical TNBC models.
- A FAM114A1-based signature demonstrated strong predictive value for ICB response in TNBC patients.
Conclusions:
- FAM114A1 is a significant driver of immune evasion and ICB resistance in triple-negative breast cancer.
- FAM114A1 represents a promising therapeutic target and a valuable predictive biomarker for ICB therapy in TNBC.
- These findings offer novel insights into TNBC immune evasion and suggest strategies to improve ICB effectiveness.
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