Next Generation Rat Models of ER+ Breast Cancer

下一代 ER 乳腺癌大鼠模型

• 批准号: 10591512
• 负责人: Yi Li
• 金额: $ 58.52万
• 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/10591512
• 关键词: Adjuvant; Behavior; Biological; Biological Markers; Brain; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer gene; Breast cancer metastasis; Cell Line; Characteristics; Circulation; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complement; Credentialing; Data; Development; Disease; Disease Progression; Drug Modelings; Drug Targeting; Ductal Epithelial Cell; Epithelium; Estrogen receptor positive; Event; Excision; Exclusion; 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/Recurrent; 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; Refractory; Research; Resistance; Resources; Risk; Role; SDZ RAD; Series; Signal Transduction; Site; Specimen; Study models; Survival Rate; TP53 gene; Therapeutic; Tumor Suppressor Proteins; Virus; Xenograft Model; Xenograft procedure; adjuvant endocrine therapy; bisphosphonate; bone; cancer initiation; cancer subtypes; clinically relevant; drug candidate; experimental study; 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：ER+乳腺癌的下一代大鼠模型 摘要：尽管雌激素受体阳性（ER+）乳腺癌（BCA）的流行率，但没有 具有免疫能力并转移到临床相关器官的哺乳动物模型 例如骨头。 ER+ BCS占BCA病例的70％，并通过手术切除治疗并调整 内分泌疗法。尽管5年生存率很高，但转移性复发的风险仍然存在于 ADE和20-40％的ER+ BCA患者最终屈服于转移性疾病，通常是骨骼。我们的 对ER+ BCA的知识有限，主要来自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临界免疫成分，而基因 工程的鼠标模型（GEMM）很少稳定地保持ER表达并依赖ER信号传导，并且 没有转移到骨头，最常见的位置。结果，关于最初的肿瘤知之甚少 ER+ BCA的创世纪过程和骨转移，这极大地阻碍了我们开发新预防的努力 策略或调整可以阻止/治疗ER+ BCA骨转移的治疗剂。我们已经开发了 通过导管内注射病毒引入遗传改变，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）在免疫能力的宿主中发展， 2）显示内分泌疗法敏感性或抗性，3）容易形成ER+转移，包括骨头 - 所有这些都是现有BCA模型中缺少的关键属性。基于这些，我们假设 乳腺癌的基于大鼠的导管内注射模型（RIIMS）忠实地概括了人类ER+ BCA 肿瘤起始，转移和治疗反应的术语。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）表征的转移行为 RIIM模型中的ER+ BCA。 （3）在概括治疗反应和 人类ER+ BCA的抗性机制。