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 | |
| State | Published - Aug 24 2012 |
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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 journal › Article
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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 -