Functional interplay between Hippo and estrogen receptor ESR1

河马与雌激素受体ESR1的功能相互作用 项目摘要/摘要 大多数乳腺癌是雌激素受体(ER阳性和ER+生长 癌症依赖于内质网功能。最常用的激素疗法是通过抑制内质网 然而，对于ER+乳腺癌的治疗，耐药性会产生。有很强的医疗保健 需要开发新的治疗方法，特别是对激素治疗抵抗的乳腺癌。雌激素 受体1(ESR1)编码内质网的主要形式，其功能已被广泛研究 作为一种核转录因子。然而，ESR1本身的转录调控较少 明白了。我们实验室的初步研究表明，ESR1的表达密切相关 由河马途径控制，该途径以其在器官大小控制和 肿瘤发生学。河马途径的核心成分LATS1/2激酶的缺失将废除 ESR1表达并抑制ER+乳腺癌细胞的生长。我们进一步发现， LATS1/2抑制癌细胞的免疫原性。这项建议是基于我们的新奇和令人兴奋的 观察。本项目的一个主要目标是揭示ESR1的分子机制 河马途径对转录的调控及ESR1在其中的功能意义 乳房组织中的河马生物学。此外，我们假设LATS抑制对ER+有两种影响 乳腺癌：通过减少ESR1的表达来抑制细胞生长；以及增强 提高癌细胞免疫原性的免疫治疗效果。第二个主要目标是 为靶向LATS1/2激酶治疗ER阳性乳腺提供科学依据 癌症。

Functional interplay between Hippo and estrogen receptor ESR1 Project Summary/Abstract The majority of breast cancers are estrogen receptor (ER positive and growth of ER+ cancer is dependent on ER function. Hormone therapy by inhibiting ER is most commonly used for ER+ breast cancer treatment, however, drug resistance develops. There is strong medical need to develop new therapy, particularly for hormone therapy resistant breast cancer. Estrogen receptor 1 (ESR1) encodes the major form of ER and has been extensively studied for its function as a nuclear transcription factor. However, the transcriptional regulation of ESR1 itself is less understood. Preliminary studies from our laboratory have shown that ESR1 expression is tightly controlled by the Hippo pathway, which is known for its role in organ size control and tumorigenesis. Deletion of LATS1/2 kinases, core components of the Hippo pathway, abolishes ESR1 expression and inhibits growth of ER+ breast cancer cells. We further discovered that LATS1/2 suppress cancer cell immunogenicity. This proposal is based on our novel and exciting observations. A major goal of this project is to reveal the molecular mechanism of ESR1 transcription regulation by the Hippo pathway and the functional significance of ESR1 in mediating Hippo biology in breast tissue. Furthermore, we posit that LATS inhibition has two effects on ER+ breast cancer: suppression of cell growth by reducing ESR1 expression; and enhancing the efficacy of immunotherapy by increasing cancer cell immunogenicity. The second major goal is to provide scientific basis for targeting the LATS1/2 kinases as a novel therapy for ER+ breast cancer.