Journal article
HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells
Clinical cancer research, Vol.18(24), pp.6634-6647
12/15/2012
DOI: 10.1158/1078-0432.CCR-12-1436
PMCID: PMC3593096
PMID: 23091114
Abstract
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.
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.
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.
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.
Details
- Title: Subtitle
- HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells
- Creators
- Nadire Duru - Departments of Radiation Oncology, University of California Davis School of Medicine, Sacramento, Ca 95817, USAMing FanDemet CandasCheikh MenaaHsin-Chen LiuDanupon NantajitYunfei WenKai XiaoAngela EldridgeBrett A ChromyShiyong LiDouglas R SpitzKit S LamMax S WichaJian Jian Li - University of California, Davis
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.18(24), pp.6634-6647
- Publisher
- United States
- DOI
- 10.1158/1078-0432.CCR-12-1436
- PMID
- 23091114
- PMCID
- PMC3593096
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- CA152313 / NCI NIH HHS CA133114 / NCI NIH HHS CA133402 / NCI NIH HHS R01 CA152313 / NCI NIH HHS P30 CA093373 / NCI NIH HHS R01 CA101860 / NCI NIH HHS R01 CA133402 / NCI NIH HHS R01 CA133114 / NCI NIH HHS
- Language
- English
- Date published
- 12/15/2012
- Academic Unit
- Pathology; Radiation Oncology
- Record Identifier
- 9984046903902771
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