Functional interplay between Hippo and estrogen receptor ESR1

Hippo 和雌激素受体 ESR1 之间的功能相互作用

• 批准号: 10339901
• 负责人: Kun-Liang Guan
• 金额: $ 43.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339901
• 关键词: Address; Biology; Breast Cancer Cell; Breast Cancer Treatment; Breast Cancer therapy; Development; Drug resistance; ESR1 gene; Estrogen Receptors; Estrogen receptor positive; Gene Expression Regulation; Goals; Growth; Homeostasis; Human; Immunotherapy; LATS1 gene; Laboratories; Malignant Neoplasms; Mammary Gland Parenchyma; Mediating; Medical; Molecular; Nuclear; Organ Size; Pathway interactions; Phosphotransferases; Play; Receptor Gene; Regulation; Resistance development; Role; Signal Transduction; Therapeutic Intervention; Tissues; Transcriptional Regulation; base; cancer cell; cell growth; hormone therapy; immunogenicity; malignant breast neoplasm; novel; novel therapeutics; therapy resistant; transcription factor; tumorigenesis

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.

Hippo与雌激素受体ESR1的功能相互作用 项目总结/摘要 大多数乳腺癌是雌激素受体（ER β阳性和ER+生长 癌症依赖于ER功能。通过抑制ER的激素治疗是最常用的 然而，对于ER+乳腺癌治疗，产生了耐药性。有强大的医疗 需要开发新的治疗方法，特别是对激素治疗耐药的乳腺癌。雌激素 受体1（ESR1）编码ER的主要形式，并已对其功能进行了广泛研究 作为核转录因子。然而，ESR1本身的转录调控较少， 明白我们实验室的初步研究表明，ESR1的表达是紧密相关的。 由Hippo途径控制，Hippo途径以其在器官大小控制中的作用而闻名， 肿瘤发生LATS 1/2激酶，Hippo通路的核心组分的缺失， ESR1表达并抑制ER+乳腺癌细胞的生长。我们进一步发现， LATS 1/2抑制癌细胞免疫原性。这个建议是基于我们的小说和令人兴奋的 意见。本项目的主要目的是揭示ESR1的分子机制 Hippo信号通路的转录调控及ESR1在介导Hippo信号通路中的功能意义 乳腺组织中的河马生物学。此外，我们认为LATS抑制对ER+有两种作用， 乳腺癌：通过减少ESR1表达来抑制细胞生长;并增强 通过增加癌细胞免疫原性来提高免疫治疗的功效。第二个主要目标是 为靶向LATS 1/2激酶治疗ER+乳腺癌提供科学依据 癌