FOXK2 amplification promotes breast cancer development and chemoresistance Journal Article
| Authors: | Yu, Y.; Cao, W. M.; Cheng, F.; Shi, Z.; Han, L.; Yi, J.; da Silva, E. M.; Dopeso, H.; Chen, H.; Yang, J.; Wang, X.; Zhang, C.; Zhang, H. |
| Article Title: | FOXK2 amplification promotes breast cancer development and chemoresistance |
| 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. © 2024 |
| Keywords: | signal transduction; controlled study; human cell; cancer growth; drug potentiation; nonhuman; flow cytometry; cell proliferation; mouse; gene; cell cycle progression; breast cancer; gene amplification; animal experiment; animal model; transcription factor; cytotoxicity; bacterial artificial chromosome; oncogene; fluorescence in situ hybridization; chromatin immunoprecipitation; immunoblotting; cell migration; real time polymerase chain reaction; nuclear localization signal; cell invasion; phosphoinositide dependent protein kinase 1; copy number variation; dichloroacetic acid; gene knockdown; human; female; article; rna sequencing; ic50; alpelisib; cell cycle assay; dinaciclib; mcf-7 cell line; hek293t cell line; cell proliferation assay; mda-mb-231 cell line; mcf-10a cell line; transwell assay; wound healing assay; hcc1954 cell line; foxk2; bt-549 cell line; foxk2 gene |
| Journal Title: | Cancer Letters |
| Volume: | 597 |
| ISSN: | 0304-3835 |
| Publisher: | Elsevier Ireland Ltd. |
| Date Published: | 2024-08-10 |
| Start Page: | 217074 |
| Language: | English |
| DOI: | 10.1016/j.canlet.2024.217074 |
| PROVIDER: | scopus |
| PUBMED: | 38901667 |
| PMCID: | PMC11290987 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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