NF-kB-mediated HER-2 overexpression in radioresistant breast cancer stem cells?

NF-kB 介导的 HER-2 在放射抗性乳腺癌干细胞中过度表达？

• 批准号: 7937029
• 负责人: Jian Jian Li
• 金额: $ 31.4万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937029
• 关键词: Biological Markers; Breast Cancer Cell; Breast Cancer Treatment; CD44 gene; Cancer Patient; Cancer cell line; Cell Line; Cell Nucleus; Cell Separation; Cell membrane; Cell surface; Cells; Clinic; Clone Cells; Data; Development; Diagnostic; Dose; ERBB2 gene; Epidermal Growth Factor Receptor; Failure; Family; Figs - dietary; Fluorescent Antibody Technique; Gene Expression; Goals; Growth; Heterogeneity; Image; Image Analysis; Immunohistochemistry; Laboratories; Link; Luciferases; MCF7 cell; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modality; Molecular; Monitor; Mus; NF-kappa B; Pathway interactions; Phenotype; Play; Population; Protein Family; Publishing; Radiation; Radiation Monitoring; Radiation Tolerance; Radiation therapy; Recurrence; Recurrent tumor; Relative (related person); Reporter; Reporting; Resistance; Role; Small Interfering RNA; Specimen; Staining method; Stains; Stem cells; Testing; Treatment Effectiveness; Treatment Failure; Tumor Bank; breast cancer diagnosis; cancer stem cell; cancer therapy; experience; in vivo; insight; malignant breast neoplasm; member; neoplastic cell; new therapeutic target; novel; novel diagnostics; overexpression; p65; promoter; public health relevance; response; self-renewal; therapeutic target; therapy resistant; transcription factor; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：