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

项目3总结/摘要 乳腺癌是一种异质性疾病，不同的亚型可能来自正常乳腺中不同的前体细胞。目前尚不清楚的是，我们如何以个性化的方式针对不同的癌前细胞类型来预防或拦截高危人群中的乳腺癌。我们先前结合了对BRCA 1和BRCA 2遗传性突变患者组织学正常乳腺组织的详细单细胞分析，以确定在这些易患癌症的组织中富集的异常细胞类型。该提案旨在开发模型，以确定在不同的高风险状态下预防乳腺癌的新目标，并帮助确定谁将从这些干预措施中受益。这将通过将类器官培养的进展与单细胞RNA测序、质谱细胞术和多重免疫荧光研究相结合来进行。首先，类器官将基于基于成像标记物的存在，从患乳腺癌风险增加的患者的乳腺组织中产生，重点关注MRI上的背景实质增强（BPE），作为患浸润性癌症的全球风险的指标。将使用基于组织和基于类器官的技术来确定在这种疾病状态下富集的细胞类型和解除调节的途径。其次，将评价BPE背景下DCIS女性患者的组织环境，这些患者对内分泌治疗（项目4）表现出应答和无应答。第三，高风险状态，包括在40岁之前发展三阴性乳腺癌的年轻女性，将在组织水平上评估潜在的癌症预防目标和放松管制的途径，包括通过开发T细胞-类器官共培养系统来模拟免疫监视。最后，将在患者来源的高危组织类器官模型中评估候选预防/干预策略，以确定未来乳腺癌预防自适应平台试验的潜在化合物（项目4目标4）。该项目的负责人Rosenbluth博士是一位乳腺肿瘤医学专家，拥有细胞和癌症生物学的研究背景，并在癌症预防的3D培养模型方面拥有专业知识。为该项目组建了一个专家团队，包括国际公认的乳腺癌研究专家Laura Esserman博士、世界著名分子生物学家和MammaPrint发明者Laura货车't Veer博士、临床癌症遗传学和乳腺癌预防领域的领导者Funmi Olopade博士，以及乳腺癌研究和自适应平台试验方面的其他合作者和专家。

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.