Next Generation Rat Models of ER+ Breast Cancer

下一代 ER 乳腺癌大鼠模型

• 批准号: 10464834
• 负责人: Yi Li
• 金额: $ 61.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-14 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464834
• 关键词: Adjuvant; Behavior; Biological; Biological Markers; Blood Circulation; Brain; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer gene; Breast cancer metastasis; Cell Line; Characteristics; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complement; Data; Development; Disease; Disease Progression; Drug Modelings; Drug Targeting; Ductal Epithelial Cell; Epithelial; Estrogen receptor positive; Event; Excision; Genetic; Genetically Engineered Mouse; Goals; Histopathology; Human; Immune; Immune system; Immunocompetent; Immunodeficient Mouse; In Vitro; Injections; Intervention; Investigation; Knowledge; Laboratories; Learning; Lesion; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Marrow; Metastatic Neoplasm to the Bone; Metastatic to; Micrometastasis; Modeling; Molecular; Molecular Profiling; Mus; Mutation; NF1 gene; Neoplasm Metastasis; Oncogenes; Operative Surgical Procedures; Organ; Osteoclasts; PIK3CA gene; Patients; Penetrance; Population; Prevalence; Prevention; Prevention strategy; Primary Neoplasm; Process; Property; Proteome; RAS genes; Rattus; Recurrence; Refractory; Research; Resistance; Resources; Role; SDZ RAD; Seeds; Series; Signal Transduction; Site; Specimen; Study models; Survival Rate; TP53 gene; Therapeutic; Tumor Suppressor Proteins; Virus; Xenograft Model; Xenograft procedure; adjuvant endocrine therapy; base; bisphosphonate; bone; cancer initiation; cancer subtypes; clinically relevant; drug candidate; experimental study; high risk; hormone therapy; in vivo; lymph nodes; malignant breast neoplasm; neoplastic cell; next generation; novel; novel therapeutics; premalignant; resistance mechanism; standard of care; therapeutically effective; therapy resistant; transcriptomics; treatment response; tumor; tumor initiation; tumorigenesis; tumorigenic

Title: Next Generation Rat Models of ER+ Breast Cancer Abstract: Despite the prevalence of estrogen receptor-positive (ER+) breast cancer (BCa), there are no mammalian models that are immunocompetent and metastasize spontaneously to clinically relevant organs such as bones. ER+ BCs comprise ~70% of BCa cases and are treated with surgical resection and adjuvant endocrine therapies. Although the 5-year survival rate is high, risk of metastatic recurrence persists for dec- ades, and 20-40% of ER+ BCa patients eventually succumb to metastatic disease, most often in bones. Our limited knowledge of ER+ BCa has been largely derived from oversimplified cell line models and in vitro experiments. Our available xenograft models exclude the critical immune component while genetically engineered mouse models (GEMMs) rarely stably maintain ER expression and rely on ER signaling – and none metastasize to bone, the most frequent site. As a result, very little is known about the initial tumori- genesis process and bone metastasis of ER+ BCa, which greatly impedes our effort to develop new prevention strategies or adjuvant therapeutics that can block/treat ER+ BCa bone metastasis. We have developed a series of rat ER+ BCa models by intraductal injection of viruses to introduce genetic alterations. Our preliminary data demonstrated that these rat ER+ mammary tumors: 1) developed in immunocompetent hosts, 2) showed endocrine therapy sensitivity or resistance, and 3) readily formed ER+ metastases including in bone – all of which are key properties that are lacking in existing BCa models. Based on these, we hypothesize that rat-based intraductal injection models (RIIMs) of breast cancer faithfully recapitulate human ER+ BCa in terms of tumor initiation, metastasis, and therapeutic responses. We will pursue the following three aims: (1) To characterize early progression of ER+ BCa in RIIM models. (2) To characterize the metastatic behaviors of ER+ BCa in RIIM models. (3) To credential ER+ RIIM models in recapitulating therapeutic responses and resistance mechanisms of human ER+ BCa.

标题：下一代 ER+ 乳腺癌大鼠模型 摘要：尽管雌激素受体阳性（ER+）乳腺癌（BCa）普遍存在，但目前还没有 具有免疫功能并自发转移至临床相关器官的哺乳动物模型 比如骨头。 ER+ BC 占 BCa 病例的约 70%，可通过手术切除和辅助治疗进行治疗 内分泌治疗。尽管5年生存率很高，但转移复发的风险仍然存在 ades，20-40% 的 ER+ BCa 患者最终死于转移性疾病，最常见的是骨骼。我们的 对 ER+ BCa 的有限了解很大程度上源自过于简化的细胞系模型和体外 实验。我们可用的异种移植模型排除了关键的免疫成分，同时从遗传角度 工程小鼠模型 (GEMM) 很少能稳定维持 ER 表达并依赖 ER 信号转导 – 并且 没有一个转移到骨，这是最常见的部位。因此，人们对最初的肿瘤知之甚少。 ER+ BCa的发生过程和骨转移，这极大地阻碍了我们开发新预防措施的努力 可以阻断/治疗 ER+ BCa 骨转移的策略或辅助治疗。我们开发了一个 通过导管内注射病毒引入遗传改变的一系列大鼠 ER+ BCa 模型。我们的 初步数据表明，这些大鼠 ER+ 乳腺肿瘤：1) 在免疫功能正常的宿主中发生， 2) 显示内分泌治疗敏感性或耐药性，并且 3) 容易形成 ER+ 转移，包括骨内转移 – 所有这些都是现有 BCa 模型所缺乏的关键属性。基于这些，我们假设 基于大鼠的乳腺癌导管内注射模型 (RIIM) 忠实地再现了人类 ER+ BCa 肿瘤发生、转移和治疗反应。我们将追求以下三个目标：（1） 表征 RIIM 模型中 ER+ BCa 的早期进展。 (2) 表征转移行为 RIIM 模型中的 ER+ BCa。 (3) 建立 ER+ RIIM 模型来概括治疗反应和 人 ER+ BCa 的耐药机制。