HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells

Nadire Duru; Ming Fan; Demet Candas; Cheikh Menaa; Hsin Chen Liu; Danupon Nantajit; Yunfei Wen; Kai Xiao; Angela Eldridge; Brett A. Chromy; Shiyong Li; Douglas R. Spitz; Kit S. Lam; Max S. Wicha; Jian Jian Li

doi:10.1158/1078-0432.CCR-12-1436

HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells

Nadire Duru, Ming Fan, Demet Candas, Cheikh Menaa, Hsin Chen Liu, Danupon Nantajit, Yunfei Wen, Kai Xiao, Angela Eldridge, Brett A. Chromy, Shiyong Li, Douglas R. Spitz, Kit S. Lam, Max S. Wicha, Jian Jian Li

Gynecological Oncology & Reproductive Medicine

Research output: Contribution to journal › Article › peer-review

176 Scopus citations

Abstract

Purpose: To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2-/low breast cancers. Experimental Design: HER2-expressing BCSCs (HER2+/CD44+/CD24-/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24-/low versus HER2-/CD44+/CD24-/low BCSCs was conducted with two-dimensional difference gel electrophoresis (2-D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program. Results: Compared with HER2-negative BCSCs, HER2+/CD44+/CD24-/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24-/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/MS-MS of HER2+/CD44+/CD24-/low versus HER2-/CD44+/CD24-/low BCSCs reported a unique HER2- associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2-STAT3 network was identified. Conclusion: This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy-resistant HER2^-/low breast cancer.

Original language	English (US)
Pages (from-to)	6634-6647
Number of pages	14
Journal	Clinical Cancer Research
Volume	18
Issue number	24
DOIs	https://doi.org/10.1158/1078-0432.CCR-12-1436
State	Published - Dec 15 2012

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/1078-0432.CCR-12-1436

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Duru, N., Fan, M., Candas, D., Menaa, C., Liu, H. C., Nantajit, D., Wen, Y., Xiao, K., Eldridge, A., Chromy, B. A., Li, S., Spitz, D. R., Lam, K. S., Wicha, M. S., & Li, J. J. (2012). HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells. Clinical Cancer Research, 18(24), 6634-6647. https://doi.org/10.1158/1078-0432.CCR-12-1436

@article{cade57ce38204ad19ea8514980ff0386,

title = "HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells",

abstract = "Purpose: To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2-/low breast cancers. Experimental Design: HER2-expressing BCSCs (HER2+/CD44+/CD24-/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24-/low versus HER2-/CD44+/CD24-/low BCSCs was conducted with two-dimensional difference gel electrophoresis (2-D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program. Results: Compared with HER2-negative BCSCs, HER2+/CD44+/CD24-/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24-/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/MS-MS of HER2+/CD44+/CD24-/low versus HER2-/CD44+/CD24-/low BCSCs reported a unique HER2- associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2-STAT3 network was identified. Conclusion: This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy-resistant HER2-/low breast cancer.",

author = "Nadire Duru and Ming Fan and Demet Candas and Cheikh Menaa and Liu, {Hsin Chen} and Danupon Nantajit and Yunfei Wen and Kai Xiao and Angela Eldridge and Chromy, {Brett A.} and Shiyong Li and Spitz, {Douglas R.} and Lam, {Kit S.} and Wicha, {Max S.} and Li, {Jian Jian}",

year = "2012",

month = dec,

day = "15",

doi = "10.1158/1078-0432.CCR-12-1436",

language = "English (US)",

volume = "18",

pages = "6634--6647",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

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TY - JOUR

T1 - HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells

AU - Duru, Nadire

AU - Fan, Ming

AU - Candas, Demet

AU - Menaa, Cheikh

AU - Liu, Hsin Chen

AU - Nantajit, Danupon

AU - Wen, Yunfei

AU - Xiao, Kai

AU - Eldridge, Angela

AU - Chromy, Brett A.

AU - Li, Shiyong

AU - Spitz, Douglas R.

AU - Lam, Kit S.

AU - Wicha, Max S.

AU - Li, Jian Jian

PY - 2012/12/15

Y1 - 2012/12/15

N2 - Purpose: To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2-/low breast cancers. Experimental Design: HER2-expressing BCSCs (HER2+/CD44+/CD24-/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24-/low versus HER2-/CD44+/CD24-/low BCSCs was conducted with two-dimensional difference gel electrophoresis (2-D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program. Results: Compared with HER2-negative BCSCs, HER2+/CD44+/CD24-/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24-/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/MS-MS of HER2+/CD44+/CD24-/low versus HER2-/CD44+/CD24-/low BCSCs reported a unique HER2- associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2-STAT3 network was identified. Conclusion: This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy-resistant HER2-/low breast cancer.

AB - Purpose: To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2-/low breast cancers. Experimental Design: HER2-expressing BCSCs (HER2+/CD44+/CD24-/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24-/low versus HER2-/CD44+/CD24-/low BCSCs was conducted with two-dimensional difference gel electrophoresis (2-D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program. Results: Compared with HER2-negative BCSCs, HER2+/CD44+/CD24-/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24-/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/MS-MS of HER2+/CD44+/CD24-/low versus HER2-/CD44+/CD24-/low BCSCs reported a unique HER2- associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2-STAT3 network was identified. Conclusion: This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy-resistant HER2-/low breast cancer.

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HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells

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