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

289 Citations (Scopus)

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

Fingerprint

Neoplastic Stem Cells
Interleukin-6
Breast Neoplasms
Population
Interleukin-6 Receptors
Antibodies
Gene Silencing
Trastuzumab
Neoplasm Metastasis
Phenotype
Cell Line
Growth
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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

In: Molecular Cell, Vol. 47, No. 4, 24.08.2012, p. 570-584.

Research output: Contribution to journalArticle

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
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. / Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population. In: Molecular Cell. 2012 ; Vol. 47, No. 4. pp. 570-584.
@article{e54d0ec2af5c4c26a50d14182505e6be,
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.}",
year = "2012",
month = "8",
day = "24",
doi = "10.1016/j.molcel.2012.06.014",
language = "English (US)",
volume = "47",
pages = "570--584",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84865401715&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865401715&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2012.06.014

DO - 10.1016/j.molcel.2012.06.014

M3 - Article

C2 - 22819326

AN - SCOPUS:84865401715

VL - 47

SP - 570

EP - 584

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 4

ER -