Heterogeneous Loss of GDF11 Tumor Suppression in Triple-negative Breast Cancer

项目摘要/摘要 大约85%的三阴性乳腺癌被归类为基底样癌或低位癌， 分子亚型预后特别差，治疗选择有限。三阴性乳房 癌症经常在DNA监视途径中存在突变；因此，它们的整个基因组 异质性已经被广泛地描述出来。相比之下，对电池所做的工作要少得多 三阴性乳腺癌的生物学。尽管公认的三阴性的组织学不一致性 肿瘤，我们只有一个信号类型和转录调控状态的基本清单， 可采用单个基底部样细胞和低突起细胞。这项工作的长期目标是确定和描述 三阴性乳腺癌的主要细胞间调控异质性。当前应用程序 重点关注生长分化因子11(GDF11)，这是一种在3D中异质性调节的扩散因子 克拉丁含量低的乳腺上皮细胞的器官培养。功能性GDF11生物活性在临床病例中丧失 晚期三阴性乳腺癌，并在浸润性克拉丁低和基底样癌中增加GDF11 LINES强烈抑制对基底膜ECM的侵袭。假设GDF11扮演的是一个局部的 乳房上皮暗示正常的小叶结构，这在三阴性期间被非遗传抑制 乳腺癌的进展。这项建议的目的是：1)确定信号和转录 介导GDF11诱导三阴性乳腺癌表型的机制。2)定义密钥 GDF11错误调控在三阴性肿瘤中的步骤。3)确定GDF11对 三阴性肿瘤的进展和转移定植。监管国家的多样性使 三阴性乳腺癌细胞在肿瘤进展和进化过程中迅速切换和适应 抗药性。一份完整的监管状态及其过渡清单有朝一日可能会被 重置肿瘤内调控异质性以延缓进展或耐药的新疗法。

PROJECT SUMMARY/ABSTRACT Roughly 85% of triple-negative breast cancers are categorized as basal-like or claudin-low carcinoma, molecular subtypes with especially poor prognosis and limited treatment options. Triple-negative breast cancers frequently harbor mutations in DNA-surveillance pathways; consequently, their overall genomic heterogeneity has been extensively characterized. By comparison, much less work has been done on the cell biology of triple-negative breast cancer. Despite the recognized histological nonuniformity of triple-negative tumors, we have only a rudimentary inventory of the types of signaling and transcriptional regulatory states that single basal-like and claudin-low cells can adopt. The long-term goal of this work is to identify and characterize the major cell-to-cell regulatory heterogeneities in triple-negative breast cancer. The current application focuses on growth-differentiation factor 11 (GDF11), a diffusible factor that is heterogeneously regulated in 3D organotypic cultures of claudin-low breast epithelial cells. Functional GDF11 bioactivity is lost in clinical cases of advanced triple-negative breast cancer, and addition of GDF11 to invasive claudin-low and basal-like cancer lines strongly suppresses invasion into basement membrane ECM. The hypothesis is that GDF11 acts a local breast-epithelial cue for proper lobular architecture, which is suppressed nongenetically during triple-negative breast cancer progression. The aims of this proposal are: 1) To identify the signaling and transcriptional mechanisms that mediate GDF11-induced phenotypes in triple-negative breast cancer. 2) To define the key steps of GDF11 misregulation in triple-negative neoplasms. 3) To determine the impact of GDF11 on progression and metastatic colonization of triple-negative tumors. The diversity of regulatory states enables triple-negative breast cancer cells to switch and adapt rapidly during tumor progression and the evolution of drug resistance. A complete inventory of regulatory states and their transitions could one day be harnessed by novel therapies that reset intratumor regulatory heterogeneity to delay progression or resistance.