FOXK2 amplification promotes breast cancer development and chemoresistance

Yang Yu, Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC, 20010, USA.
Wen-Ming Cao, Department of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Feng Cheng, Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC, 20010, USA.
Zhongcheng Shi, Advanced Technology Cores, Baylor College of Medicine, Houston, TX, 77030, USA.
Lili Han, Department of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Jinling Yi, Texas Children's Hospital, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
Edaise M. da Silva, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Higinio Dopeso, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Hui Chen, Department of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Jianhua Yang, 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.
Xiaosong Wang, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
Chunchao Zhang, 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@childrensnational.org.
Hong Zhang, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. Electronic address: zhangh3@mskcc.org.

Document Type

Journal Article

Publication Date

6-18-2024

Journal

Cancer letters

Volume

597

DOI

10.1016/j.canlet.2024.217074

Keywords

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

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.

Department

Pediatrics

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