In vitro models as a window to learn how to change outcomes in women at high risk of developing breast cancer

体外模型作为了解如何改变乳腺癌高危女性结局的窗口

• 批准号: 10707410
• 负责人: Jennifer M. Rosenbluth
• 金额: $ 53.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707410
• 关键词: Age; Age Distribution; Antiestrogen Therapy; Atypia; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Back; Benefits and Risks; Biological; Biopsy; Breast; Breast Cancer Prevention; Breast Cancer Prevention Trial; Breast Cancer Risk Factor; Breast Epithelial Cells; Cancer Biology; Cancer Model; Cell Lineage; Cells; Cellular biology; Characteristics; Clinic; Clinical; Coculture Techniques; Complex; Core Biopsy; Cytometry; Data; Development; Disease; Environment; Estrogen receptor positive; Excision; Family; Future; High Risk Woman; Histologic; Human; Image; Immunofluorescence Immunologic; Immunologic Surveillance; Immunological Models; Individual; Inherited; Intercept; International; Intervention; Lead; Learning; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammographic Density; Measures; Medical Oncologist; Methods; Modeling; Molecular; Mutation; New Agents; Noninfiltrating Intraductal Carcinoma; Normal Cell; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patients; Phenotype; Precancerous Conditions; Premalignant Cell; Prevention; Prevention strategy; Recording of previous events; Research; Research Personnel; Risk; Risk Reduction; Sampling; Susceptibility Gene; System; T-Cell Development; Techniques; Testing; Texture; Tissues; Translations; Woman; aggressive breast cancer; anticancer research; biobank; cancer genetics; cancer invasiveness; cancer prevention; candidate identification; cell type; experience; high risk; high risk population; hormone therapy; imaging biomarker; improved; in vitro Model; insight; malignant breast neoplasm; mammary; mammary epithelium; novel; patient screening; precision medicine; precursor cell; premalignant; prevent; racial diversity; radiological imaging; response; single cell analysis; single-cell RNA sequencing; stem cells; stressor; surveillance study; three dimensional cell culture; triple-negative invasive breast carcinoma; tumor; young woman

PROJECT 3 SUMMARY/ABSTRACT Breast cancer is a heterogeneous disease, with different subtypes likely arising from distinct precursor cells in the normal breast. What remains unknown is how we can target distinct precancerous cell types to prevent or intercept breast cancers in high-risk populations in a personalized manner. We previously combined detailed single-cell analyses of histologically normal breast tissues from patients with inherited mutations in BRCA1 and BRCA2 to identify aberrant cell types enriched in these cancer-prone tissues. This proposal seeks to develop models to identify new targets for breast cancer prevention in diverse high-risk states, and to help determine who would benefit from these interventions. This will be performed by combining advances in organoid culturing with single-cell RNA sequencing, mass cytometry, and multiplexed immunofluorescence studies. First, organoids will be generated from the breast tissue of patients at increased risk of developing breast cancer based on the presence of imaging-based markers, focusing on background parenchymal enhancement (BPE) on MRI as an indicator of global risk of developing invasive cancer. Tissue-based and organoid-based techniques will be used to determine the cell types enriched and pathways deregulated in this disease state. Second, the tissue environment of women with DCIS in the setting of BPE who demonstrate response and nonresponse to endocrine therapies (in Project 4) will be evaluated. Third, high-risk states including young women who developed triple-negative breast cancer before the age of 40 will be evaluated for potential cancer prevention targets and deregulated pathways at the tissue level, including by the development of T cell-organoid co-culture systems to model immune surveillance. Finally, candidate prevention/ intervention strategies will be assessed in patient-derived organoid models of high-risk tissues to identify potential compounds for a future adaptive platform trial for breast cancer prevention (Project 4 aim 4). The project lead, Dr. Rosenbluth, is a breast medical oncologist with a research background in cell and cancer biology and with expertise in 3D culture models of cancer prevention. An expert team has been assembled for this project including Dr. Laura Esserman, an internationally recognized expert in breast cancer research, Dr. Laura van 't Veer, world renowned molecular biologist and inventor of MammaPrint, and Dr. Funmi Olopade, a leader in clinical cancer genetics and breast cancer prevention, as well as additional collaborators and experts in aspects of breast cancer research and in adaptive platform trials.

项目3摘要/摘要 乳腺癌是一种异质性疾病，其亚型可能由正常乳房中不同的前体细胞产生。仍然未知的是我们如何以个性化的方式靶向不同的癌前细胞类型，以预防或拦截高风险种群中的乳腺癌。我们以前将来自BRCA1和BRCA2遗传突变患者的组织学正常乳腺组织的详细单细胞分析结合在一起，以鉴定富含这些易于癌症组织的异常细胞类型。该提案旨在开发模型，以确定各种高风险国家乳腺癌预防的新目标，并帮助确定谁将从这些干预措施中受益。这将通过将器官培养的进展与单细胞RNA测序，质量细胞仪和多重免疫荧光研究结合在一起来进行。首先，基于基于成像的标记的存在，患者的乳房组织将产生患有乳腺癌风险的风险，重点介绍了MRI的背景实质增强（BPE），这是全球侵入性癌症风险的指标。基于组织和基于器官的技术将用于确定在该疾病状态下富含途径的细胞类型。其次，将评估DCI的妇女在BPE环境中表现出对内分泌疗法的反应和无反应（在项目4中）的组织环境（在项目4中）。第三，在40岁之前成立了三阴性乳腺癌的年轻女性在内的第三，将评估潜在的预防癌症预防靶标和在组织水平下放松管制途径，包括通过开发T细胞 - 甲醇共培养系统来建模免疫监测。最后，将在高危组织的患者衍生器官模型中评估候选/干预策略，以鉴定预防乳腺癌预防的未来自适应平台试验的潜在化合物（项目4 AIM 4）。该项目负责人罗森布鲁斯（Rosenbluth）博士是一位乳房医学肿瘤学家，具有细胞和癌症生物学研究背景，并且在3D培养癌症预防模型中具有专业知识。该项目的一支专家团队包括劳拉·埃塞曼（Laura Esserman）博士，劳拉·埃塞曼（Laura Esserman）博士是乳腺癌研究的国际认可专家，劳拉·范·韦尔（Laura van't Veer）博士，世界知名的乳腺分子生物学家兼乳腺乳明的发明者，以及Funmi Olopade博士，临床癌症和乳腺癌预防和乳腺癌的临床癌症遗传学和乳腺癌的领导者，以及其他方面的癌症研究和乳腺癌研究和其他方面的癌症。