Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms.

Abstract

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.

• Authors: Jagdeep K Singh, Gillian Farnie, Nigel J Bundred, Bruno M Simões, Amrita Shergill, Göran Landberg, Sacha J Howell, Robert B Clarke
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 3 Pg. 643-56 (Feb 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23149820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-8
• Receptors, Interleukin-8A
• Receptors, Interleukin-8B
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukin-8 (metabolism)
• Neoplasm Grading
• Neoplasm Metastasis
• Neoplastic Stem Cells (metabolism)
• RNA Interference
• Receptor, ErbB-2 (antagonists & inhibitors, genetics, metabolism)
• Receptors, Interleukin-8A (antagonists & inhibitors, metabolism)
• Receptors, Interleukin-8B (antagonists & inhibitors, metabolism)
• Signal Transduction
• Spheroids, Cellular
• Tumor Cells, Cultured