Abstract 2032: Interleukin-8 expression inversely predicts the therapeutic effectiveness of doxorubicin and paclitaxel on triple-negative breast cancer

Abstract Background: Triple negative breast cancer is a subtype of breast cancer and exhibits highly metastatic potentials. Neoadjuvant or adjuvant chemotherapy, e.g. Anthracycline and Taxane, remains as a main regimen to treat TNBC currently. However, TNBC patients usually suffered from chemotherapy, e.g. doxorubicin and paclitaxel, owing to the lack of useful biomarkers to predict their therapeutic effectiveness. The aim of this study was made to estimate the usefulness of pro-inflammatory cytokine interleukin-8 (IL-8) for predicting the therapeutic efficacy of doxorubicin and paclitaxel in TNBC. Methods: The in silico analysis was performed to the potential biomarkers for predicting the therapeutic effectiveness on TNBC patients. Cell-based cytotoxicity assay was established to measure the half maximal inhibitory concentration (IC50) of doxorubicin and paclitaxel in the tested TNBC cells with IL-8 supplement or knockdown. Animal model was established to evaluate the therapeutic effectiveness of doxorubicin and paclitaxel on the xenograft tumors derived from TNBC cells without or with IL-8 overexpression or knockdown. Gene Set Enrichment Analysis (GSEA) was employed to predict the potential pathways associated with IL-8 upregulation in TNBC. Results: The in silico analysis demonstrated that IL-8 is a potential biomarker to predict the therapeutic outcome of TNBC patients who received doxorubicin or paclitaxel. The IL-8 supplement desensitized TNBC cell line HCC1937 that harbors a lower endogenous IL-8 expression to doxorubicin treatment but enhances its sensitivity to paclitaxel; Accordingly, the administration of doxorubicin failed to but paclitaxel effectively suppressed tumor growth of the xenograft tumors derived IL-8-overexpressing HCC1937 cells compared to the control group. In contrast, the treatment with doxorubicin dramatically inhibited but paclitaxel did not affect tumor growth of the xenograft tumors derived IL-8-silenced MDA-MB231 cells compared to the non-silencing control. GSEA results indicated that IL-8 upregulation in primary tumor of TNBC patients highly associates with the activation of E2F and NF-κB pathway. The inclusion of IL-8 protein in HCC1937 cells dramatically promoted but its knockdown in MDA-MB231 cells blocked RB phosphorylation, E2F activity and NF-κB activation. Pharmaceutical inhibition of IL-8 receptor by Reparixin or NF-κB by SN50 and BAY 11-7082 significantly reversed the IL-8-triggered doxorubicin resistant/paclitaxel sensitive responsiveness in HCC1937 cells. Conclusion: These findings demonstrated that IL-8 expression could be a useful indicator to predict the responsiveness of TNBC patients who are deciding to receive doxorubicin or paclitaxel therapy. Citation Format: Hui-Yu Lin, Yuan-Feng Lin, Hui-Wen Chiu, Ling-Ming Tseng. Interleukin-8 expression inversely predicts the therapeutic effectiveness of doxorubicin and paclitaxel on triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2032.