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

项目摘要 乳腺癌是全世界妇女中最常见的癌症。乳腺癌的基底细胞样亚型 与特别差的预后有关，但导致起源的分子机制和 这种疾病的发病机制还不完全清楚。我们的数据表明河马信号 在乳腺上皮细胞中，信号通路是细胞命运和祖细胞状态的重要调节器。中央到河马 转录调节因子雅普和TAZ（雅普/TAZ），当定位于细胞核时， 核驱动基础干细胞特征所需的转录事件。核雅普/TAZ活性是 通过肿瘤抑制激酶LATS 1/2限制，这是维持体内平衡所必需的。 乳腺上皮LATS 1/2在乳腺癌中表达下调，表明 这些激酶的失调导致乳腺癌病理学。在这项计划中，我们的目标是利用遗传 小鼠模型和原代细胞的离体分析，以确定LATS 1/2的缺失如何有助于 乳腺癌的发病机制。我们已经表明，在稳态乳腺，腔上皮细胞， 表现出活性LATS 1/2，具有受限的雅普/TAZ活性。我们的数据表明，有条件删除 LATS 1/2在乳腺腔上皮中的表达导致乳腺腔上皮内细胞群的快速增殖。 乳管值得注意的是，扩增的细胞显示出与管腔祖细胞相关的性状，管腔祖细胞是一种被提出的细胞， 基底样和三阴性乳腺癌的起源。通过血统追踪，我们的数据表明， 增殖性病变由LATS 1/2-null和LATS 1/2-WT细胞的异质混合物组成，和 显示出明显的雅普/TAZ核定位。此外，来自我们小鼠的LATS 1/2-null细胞是 当皮下注射到野生型小鼠中时能够形成肿瘤。我们在本提案中的目标是： 1)定义LATS 1/2的缺失如何影响乳腺稳态，并有助于 通过雅普/TAZ的活性治疗浸润性癌;和2）鉴定LATS 1/2的潜在治疗靶点- 无效乳腺癌使用转录谱。总的来说，我们提出的研究将提供至关重要的 深入了解乳腺癌发展背后的分子畸变，我们希望这将导致 未来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.