Developing and credentialing murine models of ILC

本申请是根据特别利益通知（NOSI）提交的。 被确定为NOT-CA-23-045，并根据母合同R 01 CA 252378和肿瘤学 模特论坛。 浸润性小叶乳腺癌（ILC）是乳腺癌中第二常见的特殊组织学亚型， 在美国，乳腺癌每年高达40，000例，如果认为是乳腺癌， 独立的恶性肿瘤是女性中第六常见的癌症。E-钙粘蛋白（CDH 1）缺失 是ILC的特征性特征，在超过95%的病例中蛋白质水平丢失。我们 最近报道的> 30，000例乳腺癌病例的临床结果显示， 与非特殊类型（NST）相比，ILC复发晚，预后差 （一）.尽管许多研究显示独特的临床，组织病理学和分子生物学， ILC的特点，临床试验和指南大多忽视了ILC的独特方面， NST和ILC作为一种单一的疾病，一个问题，已被认识到，并提出了乳房 癌症倡导者社区 与NST相比，ILC研究不足，部分原因是模型的可用性有限， 缺乏认证来识别那些忠实地代表人类疾病的人。因此它 目前尚不清楚哪种ILC模型最适合测试临床意义 问题.我们的团队是ILC模型开发的最前沿， ILC细胞系、患者来源的类器官（PDO）和患者来源的类器官的表征 异种移植物（PDX）。我们致力于持续开发、认证和共享 ILC的新模型。作为NCI肿瘤模型论坛和NCI R 01 CACA 252378的一部分，我们 已经开发并表征了在2D和许多PDO中生长的ILC细胞系模型。在这 补充，我们将开发和认证ER+乳腺癌新小鼠模型， 研究具有临床相关ILC遗传驱动因子和突变体的转基因表达的小鼠 雌激素受体我们还将开发和认证小鼠衍生的类器官， 其他研究人员。通过这种方式，我们的目标是加速ILC研究。

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045 and under the parent award R01CA252378 and the Oncology Models Forum. Invasive lobular breast cancer (ILC) is the second most common special histological subtype of breast cancer accounting for up to 40,000 cases yearly in the US, and if considered an independent malignancy is the 6th most frequent cancer in women. Loss of E-cadherin (CDH1) is the pathognomonic feature of ILC, being lost at the protein level in over 95% of cases. We recently reported clinical outcomes in >30,000 cases of breast cancer showing that patients with ILC suffer from late recurrences and worse outcome compared to the No Special Type (NST) (1). Despite numerous studies showing unique clinical, histopathological, and molecular features of ILC, clinical trials and guidelines mostly ignore the unique aspects of ILC and treat NST and ILC as a single disease, a problem that has been recognized and voiced by the breast cancer advocate community. ILC is understudied compared to NST, in part due to the limited availability of models and to a paucity of credentialing to identify those that faithfully represent the human disease. As such, it is currently unclear which ILC models are most appropriate to test clinically meaningful questions. Our team is at the forefront of ILC model development with generation and characterization of ILC cell lines, patient-derived organoids (PDO) and patient derived xenografts (PDX). We are committed to continued development, credentialing and sharing of novel models of ILC. As part of the NCI Oncology Models Forum and NCI R01CACA252378 we have developed and characterized ILC cell line models grown in 2D and numerous PDO. In this supplement we will develop and credential novel mouse models of ER+ mammary cancer, studying mice with clinically relevant ILC genetic drivers and transgenic expression of mutant estrogen receptor. We will also develop and credential mouse-derived organoids for sue by other researchers. In this way we aim to accelerate ILC research.