Abstract
Abstract Background: Despite recent advances in treatment for some subtypes of breast cancer (BC), triple negative (TN) BC remains a therapeutic challenge due to a lack of effective targeted agents. TNBC accounts for 10-17% of all breast malignancies and is associated with younger age, more advanced stage at diagnosis, and poorer outcome when compared with other BC subtypes. Growing evidence supports that human breast cancers are driven by a small subpopulation of cells termed cancer stem cells (CSCs) with greater tumorigenic potential. CSCs contribute to tumor initiation, maintenance, metastasis, therapeutic resistance and recurrence; thus targeting CSCs is a promising therapeutic intervention. Our laboratory has previously demonstrated the importance of the inflammatory signaling molecules interleukin 6 (IL-6) and 8 (IL-8) in maintaining CSCs in several BC subtypes. Despite promising results in other subtypes, targeting IL-6 or IL-8 alone has had less success in TNBC. Thus, this study explores the effect of combination therapy consisting of dual inhibition of IL-6 and IL-8 and chemotherapy on CSCs in TNBCs. Results: Our preliminary results demonstrate that docetaxel treatment induces three and five-fold increases in IL-6 and IL-8 levels, respectively, in an in vitro culture system of the TNBC cell line SUM159, most likely due to cell death. However, addition of IL-6 or IL-8 inhibitors does not change the cytokine levels or CSC population compared to docetaxel treatment alone. We hypothesized that the tumor microenvironment is critical to regulate the effect of cytokines on tumor growth; we therefore tested our treatment regimen in a xenograft model by injecting SUM159 cells into mammary fat pad of female NOD/SCID mouse. Docetaxel treatment alone slightly reduced tumor weight compared to vehicle control (0.6±0.4g v.s. 1.07±0.4g, p=0.04), as expected. No change was seen in tumors treated with docetaxel and IL-8 inhibitor (0.8±0.2g). Docetaxel in combination with either IL-6 inhibition (0.2±0.1 g) or IL-6 and IL-8 inhibitors (0.3±0.07 g) completely blocked tumor progression during four weeks of treatment (p=0.008, p=0.01 respectively compared to vehicle control). ALDEFLUOR assay was used to quantitate CSCs on these xenografts. The combination treatment of docetaxel plus IL-6 and IL-8 inhibitors decreased the CSC population compared to both vehicle control (0.7±0.3% v.s. 2.6%±0.8%, p=0.01) and docetaxel alone (0.7±0.3% v.s 2.6±0.3%, =0.001). Discussion: Our results suggest that IL-6 and IL-8 inhibition in combination with chemotherapy can inhibit growth of TNBC possibly by targeting the CSC population. The addition of IL-6 and IL-8 inhibition to chemotherapy may be a promising therapeutic approach for treating TNBC patients. Citation Format: Yajing Liu, Leonel Hernandez-Aya, April Davis, Max Wicha, Monika Burness. Interleukin 6 and interleukin 8 inhibitors, when used in combination with docetaxel, inhibit tumor progression in mouse model of triple-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3893. doi:10.1158/1538-7445.AM2014-3893
Published Version
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