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: 8310068
• 负责人: Jian Jian Li
• 金额: $ 30.23万
• 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/8310068
• 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; Fluorescent Antibody Technique; Gene Expression; Goals; Growth; Health; 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; 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）： 放射疗法仍然是主要的抗癌方式。最近的技术发展显着提高了肿瘤剂量递送的精度，从而使放射疗法成为肿瘤生长控制的更有效的方法。但是，由于辐射引起的适应性反应，这种治疗的有效性可能会严重损害肿瘤。肿瘤异质性已记录在辐射诱导的细胞再生和放射线抗性中起关键作用。在诊所中，乳腺癌治疗的主要失败与HER-2/NEU（EGFR家族成员ERBB2）的过表达有关。最近的数据进一步表明，乳腺癌干细胞（具有标记CD44+/CD24-/LOW）的乳腺癌干细胞包括少于1％的总肿瘤细胞群，能够自我更新并在放射疗法中生存。 HER-2在HER-2阴性乳腺癌MCF-7细胞中强制过表达，由于转录因子NF-KB的激活而诱导放射线抗性。此外，HER-2激活的NF-KB反过来刺激了HER-2基因的表达，表明乳腺癌细胞需要放射疗法所需的循环样HER-2-NF-KB-HER-2途径。 HER-2在辐照的异种移植肿瘤中诱导，重要的是，HER-2优选与CD44+共激活，但与CD24-/低/低/低/低的辐照异种移植肿瘤和乳腺癌细胞中的乳腺癌细胞一起以分数分数存活。对144名乳腺癌患者的总共180例肿瘤的免疫组织化学分析表明，HER-2阳性细胞的数量与CD44+的数量成正比，但与CD24- /低细胞无关，而在复发性入侵肿瘤中更频繁地检测到HER-2。因此，从放射性细胞系，异种移植肿瘤和乳腺癌标本中获得的所有结果都证明了放射性乳腺癌干细胞的新的且潜在的重要特征。拟议的研究的中心假设是，自适应放射率是由于NF-KB介导的HER-2过表达引起的辐射诱导的乳腺癌干细胞的重生引起的。该应用将测试和验证这种辐射耐药性乳腺癌干细胞的新型生物标志物，即NF-KB p65+/HER+/CD44+/CD24-/LOW，以识别和重新敏感性辐射耐药性乳腺癌细胞。有三个特定的目的：目标1，检测和确认放射性乳腺癌干细胞特征，P65+/HER-2+/CD44+/CD24-/低辐射耐药性乳腺癌细胞； AIM 2，以测试HER-2/CD44+是一​​种新型的敏感细胞表面生物标志物，可通过体内小鼠成像分析检测辐射耐乳腺癌干细胞；和目标3，以表征特征p65+/her-2+/cd44+/cd24-/low and Low and Low and Low and radiesistance在病理诊断的乳腺癌中。公共卫生相关性：使用新型细胞表面标记来阐明放射性乳腺癌干细胞，将提供肿瘤适应性抗性的关键见解。 p65+/HER-2+/CD44+/CD24-/LOW的辐射耐药性乳腺癌干细胞的新特征（如果鉴定）将有效地检测和重新敏感性辐射耐药性乳腺癌细胞，从而显着提高乳腺癌患者的总体治疗率。