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

项目总结/摘要 大约85%的三阴性乳腺癌被归类为基底样癌或低密蛋白癌， 分子亚型，预后特别差，治疗选择有限。三阴性乳腺 癌症经常在DNA监视途径中携带突变;因此，它们的整体基因组 异质性已被广泛表征。相比之下，在细胞上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均匀性 肿瘤，我们只有一个基本的清单类型的信号和转录调节状态， 可采用单个基底细胞样和低密蛋白细胞。这项工作的长期目标是确定和表征 三阴性乳腺癌中主要的细胞间调节异质性。当前应用程序 重点是生长分化因子11（GDF 11），一种在3D中不均匀调节的扩散因子 低密蛋白乳腺上皮细胞的器官型培养物。在临床病例中功能性GDF 11生物活性丧失 晚期三阴性乳腺癌，以及将GDF 11添加到侵袭性claudin低和基底细胞样癌 lines强烈抑制对基底膜ECM的侵袭。假设GDF 11是一个局部的 乳腺上皮提示适当的小叶结构，在三阴性期间受到非遗传性抑制 乳腺癌进展。本研究的主要目的是：1）确定信号转导和转录途径， 在三阴性乳腺癌中介导GDF 11诱导的表型的机制。2)定义键 三阴性肿瘤中GDF 11失调的步骤。3)为了确定GDF 11对 三阴性肿瘤的进展和转移定植。监管国家的多样性使得 三阴性乳腺癌细胞在肿瘤进展和乳腺癌的演变过程中迅速转换和适应， 耐药性有一天，监管状态及其过渡的完整清单可以通过以下方式加以利用： 重置肿瘤内调节异质性以延迟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.