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: 10573162
• 负责人: Jing Yang
• 金额: $ 42.57万
• 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/10573162
• 关键词: Address; Biology; Breast Cancer Cell; Breast Cancer Treatment; Breast Cancer therapy; Development; ESR1 gene; Estrogen Receptors; Estrogen decline; 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; Role; Signal Transduction; Therapeutic Intervention; Tissues; Transcriptional Regulation; cancer cell; cell growth; drug resistance development; 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 和雌激素受体 ESR1 之间的功能相互作用 项目概要/摘要 大多数乳腺癌是雌激素受体（ER 阳性且 ER+ 生长） 癌症取决于 ER 功能。最常用的是抑制 ER 的激素疗法 然而，对于 ER+ 乳腺癌治疗，会产生耐药性。有雄厚的医疗实力 需要开发新的疗法，特别是针对激素疗法耐药的乳腺癌。雌激素 受体 1 (ESR1) 编码 ER 的主要形式，其功能已被广泛研究 作为核转录因子。但ESR1本身的转录调控作用较少 明白了。我们实验室的初步研究表明ESR1表达紧密 由 Hippo 通路控制，该通路以其在器官大小控制和 肿瘤发生。删除 LATS1/2 激酶（Hippo 通路的核心成分）可消除 ESR1 表达并抑制 ER+ 乳腺癌细胞的生长。我们进一步发现 LATS1/2 抑制癌细胞免疫原性。这个提案是基于我们新颖而令人兴奋的 观察。该项目的一个主要目标是揭示ESR1的分子机制 Hippo 通路的转录调控及 ESR1 在介导中的功能意义 乳腺组织中的河马生物学。此外，我们假设 LATS 抑制对 ER+ 有两个影响 乳腺癌：通过降低 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 LATS1/2 激酶作为 ER+ 乳腺的新型疗法提供科学依据 癌症。