Regulation of Basal-Like and Her2+ Breast Cancer Phenotypes by IKK/NF-kappaB

IKK/NF-kappaB 对 Basal-Like 和 Her2 乳腺癌表型的调节

• 批准号: 8205037
• 负责人: ALBERT Sidney BALDWIN
• 金额: $ 29.66万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205037
• 关键词: Address; African American; Animal Cancer Model; Animal Disease Models; Animal Model; Animals; Apoptosis; Breast Cancer Cell; CASP8 and FADD-like apoptosis regulating protein; Cancer Patient; Cancer cell line; Categories; Cell Line; Cell Proliferation; Cells; Clinical; Data; Development; Disease; Doxorubicin; Epidermal Growth Factor Receptor; Exhibits; Gene Activation; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Targeting; Genes; Genetic Models; Growth; Health; Hematologic Neoplasms; Heterogeneity; Human; IL8 gene; Knock-in Mouse; Malignant Neoplasms; Mammary Neoplasms; Molecular Profiling; Mus; Mutation; NF-kappa B; Oncogenic; Outcome; Pathologic; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Predictive Value; Premenopause; Property; Proteins; Regulation; Regulatory Pathway; Reporting; Resistance; Roche brand of trastuzumab; Role; Sampling; Signal Pathway; Signal Transduction; Sirolimus; Solid Neoplasm; Subgroup; TLR2 gene; Testing; Therapeutic; Transgenic Mice; Tumor Cell Line; Tumor Subtype; Tumor-Derived; Woman; Work; Xenograft procedure; base; cancer cell; cancer therapy; cancer type; cell growth; chemotherapy; human FRAP1 protein; human tissue; inhibitor/antagonist; insight; interest; malignant breast neoplasm; neoplastic cell; novel therapeutics; outcome forecast; p65; research study; response; therapy development; transcription factor; tumor; tumor initiation; tumor progression

DESCRIPTION (provided by applicant): Clinical/pathological observations of breast tumor heterogeneity have now been confirmed at the gene expression level with the characterization of distinct tumor subtypes. ER-negative cancer comprises at least two distinct subtypes: the Her2+ subtype and the basal-like subtype. The basal-like breast cancer phenotype is more prevalent among premenopausal African-American cancer cases. Our gene expression analysis reveals that many basal-like breast cancers express genes that are known to be regulated by the transcription factor NF-?B. Recently it has been reported that basal-like cancers exhibit activation of PI3K/Akt and loss of p53. The Her2+ subtype of cancer is associated with the expression of a distinct set of NF-?B-dependent genes from that found in basal-like. While Akt is critical for growth and survival of Her2+ cells, our work indicates that Akt is not involved in the activation of NF-?B in Her2+ cells while it is important in basal-like cells. --Our hypothesis is that NF-?B contributes to the oncogenic phenotype and cancer therapy resistance in both basal-like and Her2+ breast cancers through different mechanisms, and that NF-?B activation in these cancers occurs by different pathways. We hypothesize that different forms of NF-?B are activated in these two types of breast cancers leading to different target gene expression. Additionally, we explore the control of Akt in these cells through an IKK1-mTORC2 mechanism. Furthermore, our data demonstrate that mouse breast tumors reflect many of the phenotypes of human tumors. Thus, we propose that these animal models can be used to test genetically the involvement of the IKK/NF-?B pathway in tumor initiation and progression, and used for analysis of therapies that block NF-?B activation or other key regulatory signaling. We are unaware of any study utilizing an animal model of basal-like cancer to address a role for IKK/NF-?B in the disease. There is one very limited knock-in study analyzing an involvement of IKK1 in Her2+ cancer. Drug studies are limited to xenografts and are quite limited regarding specific inhibitors, and do not focus on dual roles of IKK1 and IKK2. --To test our hypotheses, we propose to: (i) analyze basal-like cancer cells, animal models, and human tissue for mechanisms associated with the activation of NF-?B and target gene expression, and determine the effects of inhibitors that target these and other relevant pathways, (ii) characterize Her2+ cancer cell lines, animal tumors, and human tissue for activation of NF-:B, target gene expression, and onco-phenotypes, along with parallel inhibitor studies, with an additional approach to address Herceptin resistance, and (iii) test animal models for basal-like and Her2+ cancers for the roles of NF-?B/IKK components and specific gene targets for the development and progression of the cancers. Determine if highly specific inhibitors of IKK, mTOR, and possibly EGFR can suppress or revert growth of animal-derived tumors and/or sensitize to chemotherapy. These studies will provide insight into the development and oncogenic phenotypes of two key breast tumor subtypes and have the potential for the development of new therapeutic options for these diseases.

描述（由申请人提供）：乳腺肿瘤异质性的临床/病理学观察现已在基因表达水平上得到证实，并具有不同肿瘤亚型的特征。 ER阴性癌症包含至少两种不同的亚型：Her2+亚型和基底样亚型。基底样乳腺癌表型在绝经前非裔美国癌症病例中更为普遍。我们的基因表达分析表明，许多基底样乳腺癌表达已知受转录因子 NF-κB 调节的基因。最近有报道称，基底样癌表现出 PI3K/Akt 的激活和 p53 的缺失。癌症的 Her2+ 亚型与一组与基底细胞样中发现的不同的 NF-κB 依赖性基因的表达相关。虽然 Akt 对于 Her2+ 细胞的生长和存活至关重要，但我们的工作表明，Akt 不参与 Her2+ 细胞中 NF-κB 的激活，而它在基底样细胞中很重要。 --我们的假设是，NF-κB 通过不同的机制导致基底样乳腺癌和 Her2+ 乳腺癌的致癌表型和癌症治疗耐药性，并且这些癌症中的 NF-κB 激活通过不同的途径发生。我们假设不同形式的 NF-κB 在这两种类型的乳腺癌中被激活，导致不同的靶基因表达。此外，我们还通过 IKK1-mTORC2 机制探索 Akt 在这些细胞中的控制。此外，我们的数据表明小鼠乳腺肿瘤反映了人类肿瘤的许多表型。因此，我们建议这些动物模型可用于从基因角度测试 IKK/NF-κB 通路在肿瘤发生和进展中的参与情况，并用于分析阻断 NF-κB 激活或其他关键调节信号传导的疗法。我们不知道有任何研究利用基底细胞样癌动物模型来探讨 IKK/NF-κB 在该疾病中的作用。有一项非常有限的敲入研究分析了 IKK1 在 Her2+ 癌症中的作用。药物研究仅限于异种移植，并且关于特定抑制剂的研究非常有限，并且不关注 IKK1 和 IKK2 的双重作用。 --为了检验我们的假设，我们建议：(i) 分析基底样癌细胞、动物模型和人体组织，了解与 NF-κB 激活和靶基因表达相关的机制，并确定针对这些途径和其他相关途径的抑制剂的作用，(ii) 表征 Her2+ 癌细胞系、动物肿瘤和人体组织的 NF-:B 激活、靶基因表达和肿瘤表型， 与平行的抑制剂研究一起，采用另一种方法来解决赫赛汀耐药性，(iii) 测试基底样癌和 Her2+ 癌症的动物模型，以了解 NF-κB/IKK 成分和特定基因靶标在癌症发生和进展中的作用。确定 IKK、mTOR 和可能的 EGFR 的高度特异性抑制剂是否可以抑制或恢复动物源性肿瘤的生长和/或对化疗敏感。这些研究将深入了解两种关键乳腺肿瘤亚型的发展和致癌表型，并有可能为这些疾病开发新的治疗方案。