P3-17-04: CXCR1/2 Regulates Human Breast Cancer Stem Cell Activity Via EGFR/HER2−Dependent and -Independent Pathway
| Autor: | Robert Clarke, Gillian Farnie, Nigel J Bundred, JK Singh |
|---|---|
| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Cancer Research. 71:P3-17 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.sabcs11-p3-17-04 |
| Popis: | Background Increasing evidence suggests that breast cancers are sustained by breast cancer stem cells (CSCs). Interleukin-8 (IL-8) via its cognate receptors, CXCR1 and CXCR2, and HER2 regulate CSC activity. Cytokine receptors can trans-activate members of the epidermal growth factor receptor (EGFR) family in normal and malignant tissue. The aims of this study were to determine (1) the effect of the IL-8-CXCR1/2 signalling pathway on human breast CSC activity, (2) the effect of CXCR1/2 inhibition in combination with EGFR/HER-2 inhibition on CSC activity and (3) the interaction of CXCR1/2 and EGFR/HER2 in breast cancer. Methods: Human breast cancer cell lines used were HER2−18 and SKBR3 (both HER2 over-expressing). Primary human breast cancer cells were extracted from metastatic samples (pleural effusion n=4; ascites n=5; local recurrence n=1) and invasive breast cancers (n=1). CSC activity was investigated in vitro using the mammosphere assay. Mammosphere forming efficiency (MFE) was determined by dividing the number of mammospheres >60μm in diameter divided by the number of cells seeded and expressed as a percentage. Data is represented as mean MFE ± standard error of mean normalised to control. Statistical significance (P) was determined using Mann-Whitney U test (2-tailed). Inhibitors used were SCH563705 (a CXCR1/2 inhibitor; 100nM), Lapatinib (an EGFR/HER-2 inhibitor; 1–10μM) and Gefitinib (an EGFR inhibitor; 1μM). Results: IL-8 (100ng/ml) increased HER2−18 mean MFE from 1±0.05% to 1.20±0.04%; 19.5% increase; P=0.0061. This effect was reduced by SCH563705 (from 1.20±0.04% to 0.70±0.05; 41.7% reduction; P=0.0001) and Lapatinib (from 1.20±0.04% to 0.51±0.04; 57.5% reduction; P IL-8 (100ng/ml) increased mean MFE of primary human breast cancer cells from 1±0.03% to 1.43±0.06%; 42.9% increase; P Conclusions: IL-8/CXCR1/2 regulates the activity of human breast CSCs. Lapatinib inhibited IL-8 signalling suggesting that CXCR1/2 signal transduction involves an EGFR/HER2−dependent pathway. Targeting CXCR1/2 adds to the efficacy of targeting HER2 in HER2−over-expressing human breast CSCs through inhibition of an EGFR/HER2−independent pathway. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-04. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|