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: 8116556
• 负责人: Jian Jian Li
• 金额: $ 30.55万
• 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/8116556
• 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）： 放射治疗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输送的精度，使放射治疗成为控制肿瘤生长的更有效的方法。然而，由于辐射诱导的适应性反应，这种治疗的有效性可能会受到肿瘤耐药性的严重影响。据记载，肿瘤异质性在辐射诱导的细胞再增殖和放射抗性中发挥着关键作用。临床上，乳腺癌治疗的主要失败与HER-2/neu（ErbB2，EGFR家族成员）的过度表达有关。最近的数据进一步表明，占肿瘤细胞总数不到 1% 的乳腺癌干细胞（具有 CD44+/CD24-/低标记的 CSC）能够自我更新并在放射治疗后存活。 HER-2 阴性乳腺癌 MCF-7 细胞中 HER-2 的强制过度表达会由于转录因子 NF-kB 的激活而诱导放射抗性。此外，HER-2激活的NF-kB反过来又刺激HER-2基因表达，表明乳腺癌细胞在放疗中存活所需的环状HER-2-NF-kB-HER-2途径。 HER-2 在受辐射的异种移植肿瘤中被诱导，重要的是，在受辐射的异种移植肿瘤和在分次剂量的辐射下存活的乳腺癌细胞中，HER-2 优选与 CD44+ 共同激活，但不与 CD24-/low 共同激活。对 144 名乳腺癌患者共 180 个肿瘤的免疫组织化学分析显示，HER-2 阳性细胞数量与 CD44+ 细胞数量成比例相关，但与 CD24-/low 细胞数量无关，并且 HER-2 在复发性侵袭性肿瘤中更常见。肿瘤。因此，从抗辐射细胞系、异种移植肿瘤和乳腺癌标本中获得的所有结果都证明了抗辐射乳腺癌干细胞的一个新的、潜在的重要特征。该研究的中心假设是，适应性放射抗性是由 NF-kB 介导的 HER-2 过度表达导致的乳腺癌干细胞的辐射诱导再增殖引起的。该应用将测试和验证这种新型抗辐射乳腺癌干细胞生物标志物，即 NF-kB p65+/HER+/CD44+/CD24-/low，以识别抗辐射乳腺癌细胞并使其重新敏感。具体目标有3个： 目标1，检测并确认抗放射乳腺癌干细胞特征，抗放射乳腺癌细胞中的p65+/HER-2+/CD44+/CD24-/low；目标2，通过体内小鼠成像分析测试HER-2/CD44+是一​​种新型敏感细胞表面生物标志物，用于检测放射抗性乳腺癌干细胞；目标 3，表征病理诊断乳腺癌的 p65+/HER-2+/CD44+/CD24-/低特征和放射抗性。公共健康相关性：使用新型细胞表面标记物阐明放射抗性乳腺癌干细胞将为肿瘤适应性抵抗提供重要见解。抗辐射乳腺癌干细胞 p65+/HER-2+/CD44+/CD24-/low 的新特征如果被发现，将有望提供一种有效的方法来检测抗辐射乳腺癌细胞并使其重新敏感，从而可能显着提高整体治愈率乳腺癌患者的比例。