Over 50% of all patients with cancer are treated with radiotherapy. However, radiotherapy is often insufficient as a monotherapy and requires a nontoxic radiosensitizer. Squalene epoxidase (SQLE) controls cholesterol biosynthesis by converting squalene to 2,3-oxidosqualene. Given that SQLE is frequently overexpressed in human cancer, this study investigated the importance of SQLE in breast cancer and non–small cell lung cancer (NSCLC), two cancers often treated with radiotherapy. SQLE-positive IHC staining was observed in 68% of breast cancer and 56% of NSCLC specimens versus 15% and 25% in normal breast and lung tissue, respectively. Importantly, SQLE expression was an independent predictor of poor prognosis, and pharmacologic inhibition of SQLE enhanced breast and lung cancer cell radiosensitivity. In addition, SQLE inhibition enhanced sensitivity to PARP inhibition. Inhibition of SQLE interrupted homologous recombination by suppressing ataxia-telangiectasia mutated (ATM) activity via the translational upregulation of wild-type p53-induced phosphatase (WIP1), regardless of the p53 status. SQLE inhibition and subsequent squalene accumulation promoted this upregulation by triggering the endoplasmic reticulum (ER) stress response. Collectively, these results identify a novel tumor-specific radiosensitizer by revealing unrecognized cross-talk between squalene metabolites, ER stress, and the DNA damage response. Although SQLE inhibitors have been used as antifungal agents in the clinic, they have not yet been used as antitumor agents. Repurposing existing SQLE-inhibiting drugs may provide new cancer treatments. Significance: Squalene epoxidase inhibitors are novel tumor-specific radiosensitizers that promote ER stress and suppress homologous recombination, providing a new potential therapeutic approach to enhance radiotherapy efficacy.

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This study evaluates the effectiveness of ultrasound-guided fine needle aspiration biopsy (US-FNAB) in assessing additional positive axillary lymph node (ALN) metastasis following sentinel lymph node biopsy (SLNB) in clinically ALN-negative or N1 cases, aiming to refine patient management. A multi-center, retrospective analysis included 7617 patients with cT1-2 and cN0-1, who underwent US-FNAB for ALN and proceeding to SLNB or axillary lymph node dissection (ALND). Metastatic patterns were assessed, particularly focusing on correlations with positive FNAB results and additional ALN metastasis found during ALND, with statistical significance evaluated. Of those undergoing SLNB, 97.5% exhibited macrometastasis. In the SLNB-only group, 2.4% had 3 and more than 3 positive lymph node, compared to 19.2% in the SLNB & ALND group (P < 0.01). Among ALND patients, 63.3% had positive nodes, significantly higher in those with positive FNAB (91.9% vs. 22.8%, P < 0.001). Additionally, 40.9% were found to have additional positive ALNs in patients who underwent ALND following positive SLNB, with rates significantly higher in those with positive FNAB (60.3% vs. 35.4%, P < 0.001). LVI positivity, pT2-3, SLNR > 50% and positive FNAB were independent predictors of additional ALN metastasis in patients undergoing ALND after positive SLNB (P < 0.05). The proportion of additional positivity escalated with the number of positive SLNs. US-FNAB significantly improves the detection of additional ALN metastasis, guiding more effective strategy for ALN surgical decision-making. Our findings support the incorporation of US-FNAB into clinical practice to improve patient stratification and optimize treatment outcomes in early-stage breast cancer management.

Supplementary Data from Targeting Squalene Epoxidase Interrupts Homologous Recombination via the ER Stress Response and Promotes Radiotherapy Efficacy