Radiotherapy continues to be the major anti-cancer modality. Recent technical developments significantly increase the precision of tumor dose delivery, making radiotherapy a more efficient approach for tumor growth control. However, the effectiveness of this treatment may be severely compromised by tumor resistance due to radiation-induced adaptive response. Tumor heterogeneity is documented to play a key role in radiation-induced cell repopulation and radioresistance. In clinic, the major failure of breast cancer treatment is associated with the overexpression of HER-2/neu (ErbB2, a member of EGFR family). Recent data further suggest that breast cancer stem cells (CSCs with marker CD44+/CD24-/low) consisting of less than 1% of total tumor cell population are able to self-renew and survive the radiation therapy. Enforced overexpression of HER-2 in HER-2-negative breast cancer MCF-7 cells induces radioresistance due to activation of transcription factor NF-kB. In addition, HER-2-activated NF-kB in turn stimulates HER-2 gene expression, indicating a loop-like HER-2-NF-kB-HER-2 pathway required for breast cancer cells to survive radiotherapy. HER-2 is induced in irradiated xenograft tumors and, importantly, HER-2 is preferably co-activated with CD44+ but not with CD24-/low in irradiated xenograft tumors and breast cancer cells surviving the radiation with fractionated doses. Immunohistochemistry analysis of total 180 tumors from 144 breast cancer patients revealed that the number of HER-2-positive cells is proportionally related to the number of CD44+ but not CD24- /low cells, and HER-2 was more frequently detected in the recurrent invasive tumors. Thus, all of the results obtained from radioresistant cell lines, xenograft tumors and breast cancer specimens demonstrate a new and potentially important feature of radioresistant breast cancer stem cells. The central hypothesis of the proposed study is that adaptive radioresistance is caused by radiation- induced repopulation of breast cancer stem cells due to NF-kB-mediated HER-2 overexpression. This application will test and verify this novel biomarker of radioresistant breast cancer stem cells, i.e., NF-kB p65+/HER+/CD44+/CD24-/low, to identify and re-sensitize radioresistant breast cancer cells. There are three specific aims:
Aim 1, to detect and confirm the radioresistant breast cancer stem cell feature, p65+/HER-2+/CD44+/CD24-/low in radioresistant breast cancer cells;
Aim 2, to test that HER-2/CD44+ is a novel sensitive cell surface biomarker to detect radioresistant breast cancer stem cells by in vivo mouse imaging analysis;
and Aim 3, to characterize the feature p65+/HER- 2+/CD44+/CD24-/low and radioresistance in pathologically diagnosed breast cancers.
Elucidation of radioresistant breast cancer stem cells using novel cell surface markers will provide critical insights of tumor adaptive resistance. The new feature of radioresistant breast cancer stem cells, p65+/HER-2+/CD44+/CD24-/low , if identified, will promise an efficient approach to detect and re-sensitize radioresistant breast cancer cells and thus may significantly enhance the overall cure rate of breast cancer patients.
|Candas, Demet; Qin, Lili; Fan, Ming et al. (2016) Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1. J Vis Exp :53417|
|Liu, Rui; Fan, Ming; Candas, Demet et al. (2015) CDK1-Mediated SIRT3 Activation Enhances Mitochondrial Function and Tumor Radioresistance. Mol Cancer Ther 14:2090-102|
|Nantajit, Danupon; Lin, Dong; Li, Jian Jian (2015) The network of epithelial-mesenchymal transition: potential new targets for tumor resistance. J Cancer Res Clin Oncol 141:1697-713|
|Lu, Chung-Ling; Qin, Lili; Liu, Hsin-Chen et al. (2015) Tumor cells switch to mitochondrial oxidative phosphorylation under radiation via mTOR-mediated hexokinase II inhibition--a Warburg-reversing effect. PLoS One 10:e0121046|
|Zou, June X; Duan, Zhijian; Wang, Junjian et al. (2014) Kinesin family deregulation coordinated by bromodomain protein ANCCA and histone methyltransferase MLL for breast cancer cell growth, survival, and tamoxifen resistance. Mol Cancer Res 12:539-49|
|Candas, Demet; Li, Jian Jian (2014) MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx. Antioxid Redox Signal 20:1599-617|
|Alexandrou, Aris T; Li, Jian Jian (2014) Cell cycle regulators guide mitochondrial activity in radiation-induced adaptive response. Antioxid Redox Signal 20:1463-80|
|Candas, Demet; Lu, Chung-Ling; Fan, Ming et al. (2014) Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells. Cancer Res 74:7498-509|
|Duru, Nadire; Candas, Demet; Jiang, Guochun et al. (2014) Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society. J Cancer Res Clin Oncol 140:1-14|
|Geng, Shao-Qing; Alexandrou, Aris T; Li, Jian Jian (2014) Breast cancer stem cells: Multiple capacities in tumor metastasis. Cancer Lett 349:1-7|
Showing the most recent 10 out of 15 publications