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

doi:10.1016/j.molcel.2012.06.014

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 journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	570-584
Number of pages	15
Journal	Molecular Cell
Volume	47
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2012.06.014
State	Published - Aug 24 2012
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2012.06.014

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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

Korkaya, H, Kim, GI, Davis, A, Malik, F, Henry, NL, Ithimakin, S, Quraishi, AA, Tawakkol, N, D'Angelo, R, Paulson, AK, Chung, S, Luther, T, Paholak, HJ, Liu, S, Hassan, KA, Zen, Q, Clouthier, SG & Wicha, MS 2012, 'Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population', Molecular Cell, vol. 47, no. 4, pp. 570-584. https://doi.org/10.1016/j.molcel.2012.06.014

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

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.",

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

note = "Funding Information: We thank the University of Michigan Comprehensive Cancer Center Core facilities (Vector, Flow Cytometry, and Animal Husbandry) and the pathology team for their technical help. We are also grateful to Denise Poirier for extraordinary typing assistance. This work was supported by National Institutes of Health Grants CA129765 and CA101860 to M.S.W., Komen for the Cure Research Grant KG110230 to H.K. and an Indo-U.S. fellowship to F.M. M.S.W. has financial holdings in OncoMed Pharmaceuticals and receives research support from Dompe. ",

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doi = "10.1016/j.molcel.2012.06.014",

language = "English (US)",

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T1 - Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population

AU - Korkaya, Hasan

AU - Kim, Gwang Il

AU - Davis, April

AU - Malik, Fayaz

AU - Henry, N. Lynn

AU - Ithimakin, Suthinee

AU - Quraishi, Ahmed A.

AU - Tawakkol, Nader

AU - D'Angelo, Rosemarie

AU - Paulson, Amanda K.

AU - Chung, Susan

AU - Luther, Tahra

AU - Paholak, Hayley J.

AU - Liu, Suling

AU - Hassan, Khaled A.

AU - Zen, Qin

AU - Clouthier, Shawn G.

AU - Wicha, Max S.

N1 - Funding Information: We thank the University of Michigan Comprehensive Cancer Center Core facilities (Vector, Flow Cytometry, and Animal Husbandry) and the pathology team for their technical help. We are also grateful to Denise Poirier for extraordinary typing assistance. This work was supported by National Institutes of Health Grants CA129765 and CA101860 to M.S.W., Komen for the Cure Research Grant KG110230 to H.K. and an Indo-U.S. fellowship to F.M. M.S.W. has financial holdings in OncoMed Pharmaceuticals and receives research support from Dompe.

PY - 2012/8/24

Y1 - 2012/8/24

N2 - 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.

AB - 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.

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

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