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

描述（由申请方提供）：乳腺肿瘤异质性的临床/病理学观察结果现已在基因表达水平得到证实，具有不同肿瘤亚型的特征。ER阴性癌症包括至少两种不同的亚型：Her 2+亚型和基底样亚型。基底样乳腺癌表型在绝经前非洲裔美国人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的基因是已知的转录因子NF-？B。最近有报道称，基底样癌表现出PI 3 K/Akt的激活和p53的丢失。Her 2+亚型的癌症与一组不同的NF-？依赖于B的基因从基底样中发现。虽然Akt对Her 2+细胞的生长和存活至关重要，但我们的工作表明Akt不参与NF-？B在Her 2+细胞中是重要的，而在基底样细胞中是重要的。--我们的假设是NF-？B通过不同的机制导致基底细胞样和Her 2+乳腺癌的致癌表型和癌症治疗抗性，NF-？这些癌症中的B活化通过不同的途径发生。我们假设不同形式的NF-？B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，我们还探索了通过IKK 1-mTORC 2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许多人类肿瘤的表型。因此，我们建议，这些动物模型可以用来测试基因的IKK/NF-？B途径在肿瘤发生和发展中的作用，并用于分析阻断NF-？B激活或其它关键调节信号。我们不知道有任何研究利用基底细胞样癌动物模型来解决IKK/NF-？的作用。疾病中的B。有一个非常有限的敲入研究分析IKK 1参与Her 2+癌症。药物研究仅限于异种移植物，并且关于特异性抑制剂的研究非常有限，并且不关注IKK 1和IKK 2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与NF-？B和靶基因表达，并确定靶向这些和其他相关途径的抑制剂的作用，（ii）表征Her 2+癌细胞系、动物肿瘤和人类组织的NF-：B激活、靶基因表达和肿瘤表型，沿着平行抑制剂研究，以及解决赫赛汀耐药性的额外方法，和（iii）测试基底样和Her 2+癌症的动物模型中NF-？B/IKK组分和癌症发生和发展的特异性基因靶点。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逆转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。

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.