FOXK2 amplification promotes breast cancer development and chemoresistance.

Yu, Yang; Cao, Wen-Ming; Cheng, Feng; Shi, Zhongcheng; Han, Lili; Yi, Jinling; da Silva, Edaise M; Dopeso, Higinio; Chen, Hui; Yang, Jianhua; Wang, Xiaosong; Zhang, Chunchao; Zhang, Hong

Yu, Yang; Cao, Wen-Ming; Cheng, Feng; Shi, Zhongcheng; Han, Lili; Yi, Jinling; da Silva, Edaise M; Dopeso, Higinio; Chen, Hui; Yang, Jianhua; Wang, Xiaosong; Zhang, Chunchao; Zhang, Hong.

Afiliación

Yu Y; Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC, 20010, USA.
Cao WM; Department of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Cheng F; Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC, 20010, USA.
Shi Z; Advanced Technology Cores, Baylor College of Medicine, Houston, TX, 77030, USA.
Han L; Department of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Yi J; Texas Children's Hospital, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
da Silva EM; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Dopeso H; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Chen H; Department of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Yang J; Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC, 20010, USA; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20010, USA.
Wang X; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
Zhang C; Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC, 20010, USA; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20010, USA. Electronic address: czhang@child
Zhang H; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. Electronic address: zhangh3@mskcc.org.

Cancer Lett ; 597: 217074, 2024 Aug 10.

Article en En | MEDLINE | ID: mdl-38901667

ABSTRACT

ABSTRACT

Oncogene activation through DNA amplification or overexpression is a crucial driver of cancer initiation and progression. The FOXK2 gene, located on chromosome 17q25, encodes a transcription factor with a forkhead DNA-binding domain. Analysis of genomic datasets reveals that FOXK2 is frequently amplified and overexpressed in breast cancer, correlating with poor patient survival. Knockdown of FOXK2 significantly inhibited breast cancer cell proliferation, migration, anchorage-independent growth, and delayed tumor growth in a xenograft mouse model. Additionally, inhibiting FOXK2 sensitized breast cancer cells to chemotherapy. Co-overexpression of FOXK2 and mutant PI3KCA transformed non-tumorigenic MCF-10A cells, suggesting a role for FOXK2 in PI3KCA-driven tumorigenesis. CCNE2, PDK1, and ESR1 were identified as transcriptional targets of FOXK2 in MCF-7 cells. Small-molecule inhibitors of CCNE2/CDK2 (dinaciclib) and PDK1 (dichloroacetate) exhibited synergistic anti-tumor effects with PI3KCA inhibitor (alpelisib) in vitro. Inhibition of FOXK2 by dinaciclib synergistically enhanced the anti-tumor effects of alpelisib in a xenograft mouse model. Collectively, these findings highlight the oncogenic function of FOXK2 and suggest that FOXK2 and its downstream genes represent potential therapeutic targets in breast cancer.

Asunto(s)

Neoplasias de la Mama; Proliferación Celular; Resistencia a Antineoplásicos; Factores de Transcripción Forkhead; Animales; Femenino; Humanos; Ratones; Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo; Proteínas Quinasas Dependientes de 3-Fosfoinosítido/genética; Antineoplásicos/farmacología; Neoplasias de la Mama/genética; Neoplasias de la Mama/patología; Neoplasias de la Mama/tratamiento farmacológico; Neoplasias de la Mama/metabolismo; Movimiento Celular/efectos de los fármacos; Proliferación Celular/efectos de los fármacos; Quinasa 2 Dependiente de la Ciclina/genética; Quinasa 2 Dependiente de la Ciclina/metabolismo; Resistencia a Antineoplásicos/genética; Receptor alfa de Estrógeno/genética; Receptor alfa de Estrógeno/metabolismo; Factores de Transcripción Forkhead/genética; Factores de Transcripción Forkhead/metabolismo; Amplificación de Genes; Regulación Neoplásica de la Expresión Génica/efectos de los fármacos; Células MCF-7; Ratones Desnudos; Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética; Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo; Tiazoles/farmacología; Ensayos Antitumor por Modelo de Xenoinjerto

Palabras clave

Breast cancer; FOXK2; Gene amplification; Oncogene; Transcription factor

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Resistencia a Antineoplásicos / Proliferación Celular / Factores de Transcripción Forkhead Límite: Animals / Female / Humans Idioma: En Revista: Cancer Lett Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Irlanda

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