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

• Published in: Molecular cell 2012-08, Vol.47 (4), p.570-584
• Main Authors: Korkaya, Hasan, Kim, Gwang-il, Davis, April, Malik, Fayaz, Henry, N. Lynn, Ithimakin, Suthinee, Quraishi, Ahmed A., Tawakkol, Nader, D'Angelo, Rosemarie, Paulson, Amanda K., Chung, Susan, Luther, Tahra, Paholak, Hayley J., Liu, Suling, Hassan, Khaled A., Zen, Qin, Clouthier, Shawn G., Wicha, Max S.
• Format: Article
• Language: English
• Subjects: Animals; antibodies; Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents - pharmacology; breast neoplasms; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Chemokine CCL5 - genetics; Chemokine CCL5 - metabolism; Down-Regulation - genetics; Drug Resistance, Neoplasm; Female; genes; Humans; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; interleukin-6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukin-8 - genetics; Interleukin-8 - metabolism; metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; phenotype; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; stem cells; Trastuzumab
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2012.06.014

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. ► PTEN deletion in HER2+ breast tumors activates IL6 feedback loop ► IL6/NF-κB signaling induces breast cancer stem cell population with EMT phenotype ► IL6 induced breast cancer stem cells are resistant to anti-HER2 therapy ► Anti-IL6R antibody overcomes trastuzumab resistance in mouse xenograft models