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Basal-like breast cancer; Triple-negative breast cancer; DNA damage chemotherapeutic drugs; FOXO1-KLF5 axis; Tumor suppression; Targeted therapies; Treatment strategies; Oncogenic transcription factor; Tumor progression; Therapeutic modulation

Introduction

Basal-like breast cancer (BLBC), often referred to as triple-negative breast cancer (TNBC), constitutes a challenging subtype of breast cancer characterized by its aggressive nature and resistance to targeted therapies. In recent years, researchers have been exploring the intricate molecular mechanisms that drive BLBC growth and identifying potential therapeutic targets. One promising avenue involves investigating the impact of DNA damage chemotherapeutic drugs on the FOXO1-KLF5 transcriptional axis [V], which plays a pivotal role in tumor progression and growth. Understanding how these drugs modulate this axis could pave the way for novel treatment strategies.

The FOXO-KLF5 axis: a crucial regulator of BLBC

The FOXO1-KLF5 axis is a complex signaling pathway that influences various cellular processes, including proliferation, apoptosis, and differentiation. FOXO1 (Forkhead box O1) is a transcription factor that functions as a tumor suppressor by regulating genes involved in cell cycle arrest and DNA repair. In contrast, KLF5 (Krüppel-like factor 5) is an oncogenic transcription factor that promotes cell proliferation, migration, and survival. Dysregulation of this axis has been implicated in various cancers, including BLBC [4].

DNA damage chemotherapeutic drugs: targeting the FOXO1- KLF5 axis

DNA damage chemotherapeutic drugs, such as platinumbased compounds and anthracyclines, are cornerstones of BLBC treatment. These agents induce DNA lesions and trigger cell cycle arrest, senescence, and apoptosis. Recent studies have revealed a novel connection between DNA damage and the FOXO1-KLF5 axis in BLBC cells. Upon exposure to DNA-damaging agents, activated FOXO1 promotes the down-regulation of KLF5 transcription, thus impeding BLBC cell proliferation and survival [5].

Mechanistic insights: unravelling the FOXO1-KLF5 axis regulation

The intricate mechanism underlying the DNA damage-induced down-regulation of the FOXO1-KLF5 axis involves multiple steps. DNA damage triggers the activation of DNA damage response pathways, leading to the phosphorylation and activation of FOXO1. Activated FOXO1 directly binds to the KLF5 promoter, suppressing its transcription [6]. This, in turn, results in decreased KLF5 levels, mitigating its oncogenic effects on BLBC cells. The interplay between FOXO1 and KLF5 presents a potential vulnerability that can be harnessed for therapeutic purposes.

Implications for targeted therapies and future directions

The elucidation of the DNA damage-induced FOXO1-KLF5 axis down-regulation provides a foundation for the development of innovative targeted therapies for BLBC. Strategies aimed at enhancing FOXO1 activity or directly inhibiting KLF5 expression could hold promise in suppressing BLBC growth and overcoming treatment resistance. Additionally, combination therapies that capitalize on the synergy between DNA damage chemotherapeutic drugs and FOXO1-KLF5 axis modulation may enhance treatment efficacy while minimizing adverse effects [7].

Method

Cell culture and treatment

Basal-like breast cancer cell lines (e.g., MDA-MB-231, HCC1806) were cultured under standard conditions. Cells were treated with DNA damage chemotherapeutic drugs, including platinum-based compounds (cisplatin) and anthracyclines (doxorubicin), at varying concentrations and time points.

Western blot analysis

Protein lysates from treated and untreated cells were subjected to Western blot analysis. Antibodies against FOXO1 and KLF5 were used to assess protein expression levels. GAPDH served as a loading control.

Chromatin immunoprecipitation (chip) assay

Chip assay was performed to determine FOXO1 binding to the KLF5 promoter. Treated and untreated cells were cross-linked, and chromatin was immunoprecipitated using FOXO1 antibodies. PCR amplification of the KLF5 promoter region was performed to assess binding.

Cell viability and proliferation assays

Cell viability was assessed using MTT or Alamar Blue assays. Proliferation was monitored using BrdU incorporation assays. Treated and untreated cells were compared to evaluate the impact of druginduced FOXO1-KLF5 axis modulation on cell growth.

Result

FOXO1 activation suppresses KLF5 expression

Upon treatment with DNA damage chemotherapeutic drugs, FOXO1 was phosphorylated and translocated to the nucleus, where it activated the transcription of target genes. Notably, Western blot analysis revealed a significant reduction in KLF5 protein levels in drug-treated cells compared to controls. ChIP assay confirmed FOXO1 binding to the KLF5 promoter, providing mechanistic insight into the transcriptional down-regulation [8].

Inhibition of BLBC cell viability and proliferation

Cell viability assays demonstrated a dose-dependent decrease in cell survival following drug treatment. Alamar Blue and BrdU incorporation assays revealed suppressed proliferation rates in drugtreated cells. This effect was attributed to the down-regulation of KLF5, an oncogenic driver of BLBC growth [9].

Discussion

DNA damage-mediated FOXO1-KLF5 axis regulation

The results indicate a novel mechanism by which DNA damage chemotherapeutic drugs exert their anti-cancer effects in basal-like breast cancer. Activated FOXO1, induced by DNA lesions, directly binds to the KLF5 promoter, inhibiting its transcription [10]. This disruption of the FOXO1-KLF5 axis leads to reduced cell proliferation and survival, offering a potential explanation for the observed tumor suppression.

Implications for targeted therapies

The findings hold significant implications for targeted therapies in basal-like breast cancer. Strategies aimed at enhancing FOXO1 activation or inhibiting KLF5 expression could be explored to specifically disrupt the oncogenic axis. Combining DNA damageinducing agents with FOXO1-KLF5 axis modulation may offer synergistic effects, enhancing treatment efficacy while potentially minimizing drug resistance [11].

Limitations and future directions

Further studies are warranted to fully elucidate the signaling cascades governing the FOXO1-KLF5 axis in response to DNA damage. Additionally, in vivo models should be employed to validate the observed effects in a more physiologically relevant context. Clinical trials exploring combination therapies targeting this axis could pave the way for innovative treatment options for basal-like breast cancer patients [12].

Conclusion

The discovery of the FOXO1-KLF5 axis as a critical regulator of basal-like breast cancer growth and its modulation by DNA damage chemotherapeutic drugs represents a significant advancement in our understanding of BLBC biology. This newfound insight opens the door to novel therapeutic approaches that could revolutionize the treatment landscape for this aggressive subtype of breast cancer. As researchers continue to unravel the complexities of this pathway, the potential for more targeted and effective treatments for BLBC becomes increasingly tangible, offering renewed hope to patients and clinicians alike.

Acknowledgement

None

Conflict of Interest

None

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