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PURPOSE: Breast cancer stem-like cells (CSC) are an important therapeutic target as they are predicted to be responsible for tumor initiation, maintenance, and metastases. Interleukin (IL)-8 is upregulated in breast cancer and is associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy. EXPERIMENTAL DESIGN: CSC activity of metastatic and invasive human breast cancers (n = 19) was assessed ex vivo using the mammosphere colony-forming assay. RESULTS: Metastatic fluid IL-8 level correlated directly with mammosphere formation (r = 0.652; P < 0.05; n = 10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n = 17). IL-8 induced activation of EGFR/HER2 and downstream signaling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, phosphoinositide 3-kinase (PI3K), or MEK. Furthermore, lapatinib, which targets EGFR/HER2, inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers. CONCLUSIONS: These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and show that IL-8/CXCR1/2 signaling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients.

Original publication

DOI

10.1158/1078-0432.CCR-12-1063

Type

Journal article

Journal

Clin Cancer Res

Publication Date

01/02/2013

Volume

19

Pages

643 - 656

Keywords

Breast Neoplasms, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Interleukin-8, Neoplasm Grading, Neoplasm Metastasis, Neoplastic Stem Cells, RNA Interference, Receptor, Epidermal Growth Factor, Receptor, ErbB-2, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Signal Transduction, Spheroids, Cellular, Tumor Cells, Cultured