Determining the roles of the Hippo pathway kinases LATS1 and LATS2 in mammary gland homeostasis and disease

项目摘要 乳腺癌是全世界女性中最常见的癌症。乳腺癌的基底细胞样亚型 与预后特别差有关，然而导致该病发生和发展的分子机制 这种疾病的发病机制还不够清楚。我们的数据显示河马信号 通路是乳腺上皮细胞命运和祖细胞状态的重要调节因子。河马中心 途径信号是转录调节因子Yap和TAZ(Yap/TAZ)，当定位于 核驱动基本干细胞特性所需的转录事件。核YAP/TAZ活动是 受肿瘤抑制因子LATS1/2的限制，这是维持细胞内环境平衡所必需的。 乳腺上皮细胞。LATS1/2在乳腺癌中的表达下调，这表明 这些激酶的失调导致了乳腺癌的病理。在这项提案中，我们的目标是使用基因 小鼠模型和体外原代细胞分析，以确定LATS1/2的丢失如何在 乳腺癌的发病机制。我们已经证明，在动态平衡的乳腺中，腔上皮细胞 显示LATS1/2活性，YAP/TAZ活性受限。我们的数据表明，有条件删除 腔内乳腺上皮中的LATS1/2导致乳腺组织内一组细胞的快速增殖 乳房导管。值得注意的是，扩增的细胞表现出与腔祖细胞相关的特征，这是一种被提议的 基底细胞样癌和三阴性乳腺癌的起源。通过血统追踪，我们的数据表明 增生性病变由LATS1/2-Null和LATS1/2-WT细胞的异质性混合物组成，以及 显示出YAP/TAZ显著的核定位。此外，来自我们的小鼠的LATS1/2零细胞是 当注射到野生型小鼠的皮下时能够形成肿瘤。我们在这项建议中的目标是： 1)明确LATS1/2的缺失如何影响乳腺的动态平衡，并有助于 通过YAP/TAZ的活性；2)寻找LATS1/2的潜在治疗靶点- 使用转录图谱分析为零的乳腺癌。总体而言，我们拟议的研究将提供关键的 对乳腺癌发生的分子异常的洞察，我们希望这将导致 在未来针对这种疾病的更有效的治疗和诊断策略。

Project Summary Breast cancer is the most prevalent cancer among women worldwide. The basal-like subtype of breast cancer is associated with a particularly poor prognosis, yet the molecular mechanisms leading to the origin and pathogenesis of this disease are inadequately understood. Our data has indicated that the Hippo signaling pathway is an important regulator of cell fate and progenitor status in the mammary epithelium. Central to Hippo pathway signaling are the transcriptional regulators YAP and TAZ (YAP/TAZ), which when localized to the nucleus drive transcriptional events that are required for basal stem cell traits. Nuclear YAP/TAZ activity is restricted through the tumor suppressor kinases LATS1/2, which are required to maintain homeostasis in the mammary epithelium. LATS1/2 have been shown to be downregulated in breast cancers, suggesting that dysregulation of these kinases contributes to breast cancer pathology. In this proposal, we aim to use genetic mouse models and ex vivo analysis of primary cells to define how loss of LATS1/2 contributes to the pathogenesis of breast cancer. We have shown that in the homeostatic mammary gland, luminal epithelial cells exhibit active LATS1/2, with restricted YAP/TAZ activity. Our data demonstrate that conditional deletion of LATS1/2 in the luminal mammary epithelium leads to the rapid proliferation of a population of cells within the mammary duct. Notably, expanded cells display traits associated with luminal progenitors, a proposed cell of origin of basal-like and triple-negative breast cancers. Through lineage tracing, our data suggest that the proliferating lesions are comprised of a heterogeneous mixture of LATS1/2-null and LATS1/2-WT cells, and exhibit significant nuclear localization of YAP/TAZ. Furthermore, LATS1/2-null cells derived from our mice are capable of forming tumors when injected subcutaneously into wild-type mice. Our goals in this proposal are to: 1) define how loss of LATS1/2 affects mammary gland homeostasis and contributes to the development of invasive carcinoma through the activity of YAP/TAZ; and 2) identify potential therapeutic targets for LATS1/2- null mammary carcinomas using transcriptional profiling. Collectively, our proposed studies will provide crucial insight into the molecular aberrations underlying the development of breast cancer, which we hope will lead to more impactful treatments and diagnostic strategies for this disease in the future.