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.

河马和雌激素受体ESR1之间的功能相互作用 项目摘要/摘要 大多数乳腺癌是雌激素受体（ER阳性和ER+的生长 癌症取决于ER功能。抑制ER的激素治疗最常用 但是，对于ER+乳腺癌治疗，是耐药性的发展。有强大的医疗 需要开发新的疗法，特别是针对抗马疗法的抗乳腺癌。雌激素 受体1（ESR1）编码ER的主要形式，并且已广泛研究其功能 作为核转录因子。但是，ESR1本身的转录调节较少 理解。我们实验室的初步研究表明，ESR1表达紧密 由河马途径控制，该途径以其在器官尺寸控制中的作用而闻名 肿瘤发生。删除LATS1/2激酶，河马途径的核心成分，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抑制癌细胞免疫原性。该提议是基于我们的小说和令人兴奋的 观察。该项目的主要目标是揭示ESR1的分子机制 通过河马途径调节转录调节和ESR1介导的功能意义 乳腺组织中的河马生物学。此外，我们的海报认为LATS抑制对ER+有两种影响 乳腺癌：通过降低ESR1表达来抑制细胞生长；并增强 免疫疗法的功效通过增加癌细胞免疫原性。第二个主要目标是 为靶向LATS1/2激酶作为ER+乳房的新疗法提供科学基础 癌症。