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

描述(由申请人提供)：乳腺肿瘤异质性的临床/病理观察现已在基因表达水平得到证实，并具有不同的肿瘤亚型特征。ER阴性癌至少包括两种不同的亚型：Her2+亚型和基底样亚型。基底细胞样乳腺癌表型在绝经前的非裔美国人癌症病例中更为常见。我们的基因表达分析表明，许多基底样癌表达已知受转录因子NF-βB调控的基因。最近有报道称，基底样癌表现出PI3K/Akt的激活和P53的丢失。Her2+亚型癌症与一组不同于基底细胞样癌的依赖于核因子？B的基因的表达有关。虽然Akt对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+细胞中的核因子-βB的激活，而在基底样细胞中很重要。--我们的假设是，在基底细胞样癌和Her2+乳腺癌中，核因子-βB通过不同的机制促进肿瘤表型和抗癌治疗，并且在这些癌症中核因子-βB的激活通过不同的途径发生。我们假设，在这两种类型的乳腺癌中，不同形式的核因子-βB被激活，导致不同的靶基因表达。此外，我们还探索了通过IKK1-mTORC2机制对这些细胞中Akt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以用来从基因上测试IKK/NF-βB通路在肿瘤发生和发展中的参与，并用于分析阻断NF-βB激活或其他关键调控信号的治疗方法。我们不知道有任何研究利用基底细胞样癌的动物模型来解决IKK/核因子-βB在疾病中的作用。有一项非常有限的敲入研究分析了IKK1在Her2+癌症中的参与。药物研究仅限于异种移植，关于特定抑制剂的研究相当有限，并没有关注IKK1和IKK2的双重作用。--为了验证我们的假设，我们建议：(I)分析基底样癌细胞、动物模型和人体组织中与激活核因子-βB和靶基因表达相关的机制，并确定靶向这些和其他相关途径的抑制剂的效果；(Ii)表征Her2+癌细胞系、动物肿瘤和人类组织中激活核因子-β：B、靶基因表达和癌表型的特征，以及平行的抑制剂研究，以及解决赫赛汀耐药性的另一种方法。以及(Iii)测试基底细胞样癌和Her2+癌的动物模型，以了解核因子？B/IKK组分和特定基因靶点在癌症发生和发展中的作用。确定高度特异的IKK、mTOR和可能的EGFR抑制剂是否可以抑制或逆转动物源性肿瘤的生长和/或使化疗敏感。这些研究将提供对两种关键乳腺肿瘤亚型的发展和致癌表型的洞察，并有可能为这些疾病开发新的治疗方案。

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.