FOXK2 amplification promotes breast cancer development and chemoresistance

Cancer Lett. 2024 Aug 10:597:217074. doi: 10.1016/j.canlet.2024.217074. Epub 2024 Jun 18.

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.

Keywords: Breast cancer; FOXK2; Gene amplification; Oncogene; Transcription factor.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases / genetics
  • 3-Phosphoinositide-Dependent Protein Kinases / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Cell Movement / drug effects
  • Cell Proliferation* / drug effects
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism
  • Drug Resistance, Neoplasm* / genetics
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Forkhead Transcription Factors* / genetics
  • Forkhead Transcription Factors* / metabolism
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / genetics
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism
  • Thiazoles / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Antineoplastic Agents
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Forkhead Transcription Factors
  • interleukin binding factor
  • PDPK1 protein, human
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Thiazoles