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)的发病率很高，但目前还没有 具有免疫活性并自发转移到临床相关器官的哺乳动物模型 比如骨头。ER+BCS约占BCA病例的70%，采用手术切除和辅助治疗 内分泌疗法。虽然5年存活率很高，但转移复发的风险在12月份持续存在。 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 关于ER+BCA的有限知识主要来源于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，而从基因上 工程化小鼠模型(GEMM)很少稳定地维持ER表达并依赖ER信号-和 无骨转移，骨是最常见的部位。因此，人们对最初的图莫里知之甚少- ER+BCA的发生过程和骨转移极大地阻碍了我们开发新的预防措施 可阻断/治疗ER+BCA骨转移的策略或辅助治疗。我们已经开发出一种 通过导管内注射病毒建立大鼠ER+BCA模型，引入基因改变。我们的 初步数据表明，这些大鼠ER+乳腺肿瘤：1)发生在免疫活性宿主中， 2)对内分泌治疗敏感或耐药，3)易形成ER+转移，包括骨转移 -所有这些都是现有BCA模型所缺乏的关键属性。在此基础上，我们假设 以大鼠为基础的乳腺癌导管内注射模型(RIIM)忠实地概括了人ER+BCA在 肿瘤起始、转移和治疗反应方面的术语。我们将追求以下三个目标：(一) 研究RIIM模型中ER+BCA的早期进展。(2)研究人卵巢癌的转移行为 RIIM模型中ER+BCA。(3)证明ER+RIIM模型在总结治疗反应和 人ER+BCA耐药机制的研究