Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population

Hasan Korkaya, Gwang Il Kim, April Davis, Fayaz Malik, N. Lynn Henry, Suthinee Ithimakin, Ahmed A. Quraishi, Nader Tawakkol, Rosemarie D'Angelo, Amanda K. Paulson, Susan Chung, Tahra Luther, Hayley J. Paholak, Suling Liu, Khaled A. Hassan, Qin Zen, Shawn G. Clouthier, Max S. Wicha

Research output: Contribution to journalArticle

308 Scopus citations

Abstract

Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance.

Original languageEnglish (US)
Pages (from-to)570-584
Number of pages15
JournalMolecular Cell
Volume47
Issue number4
DOIs
StatePublished - Aug 24 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Korkaya, H., Kim, G. I., Davis, A., Malik, F., Henry, N. L., Ithimakin, S., Quraishi, A. A., Tawakkol, N., D'Angelo, R., Paulson, A. K., Chung, S., Luther, T., Paholak, H. J., Liu, S., Hassan, K. A., Zen, Q., Clouthier, S. G., & Wicha, M. S. (2012). Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population. Molecular Cell, 47(4), 570-584. https://doi.org/10.1016/j.molcel.2012.06.014