PELP1, a Novel Regulator of Estrogen Receptor

PELP1，一种新型雌激素受体调节剂

• 批准号: 8211872
• 负责人: Ratna K Vadlamudi
• 金额: $ 5.14万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211872
• 关键词: Anabolism; Aromatase Inhibitors; Biological Markers; Breast; Cancer Biology; Cell Cycle Progression; Cell Proliferation; Cell model; Cellular biology; Code; Combined Modality Therapy; Complex; Coupling; Cytoplasm; Data; Diagnosis; Disease; Disease-Free Survival; Epigenetic Process; Epithelial Cells; Estrogen Receptors; Estrogens; Event; Funding; Gene Targeting; Genetic Transcription; Genomics; Glutamic Acid; Goals; Grant; Growth; Growth Factor; Health; Histones; Hormonal; Human; In Vitro; Lead; Leucine; Malignant - descriptor; Mammary Neoplasms; Mediating; Membrane; Methodology; Molecular Biology; Neoplasm Metastasis; Pathologic Processes; Pathology; Peripheral; Phosphorylation; Physiological; Play; Proline; Proteins; Proteomics; Proto-Oncogenes; Reagent; Research; Resistance; Resistance development; Role; Selective Estrogen Receptor Modulators; Signal Pathway; Signal Transduction; Tamoxifen; Testing; Therapeutic Intervention; Transgenic Mice; Work; base; cancer therapy; chromatin modification; clinically significant; histone methyltransferase; histone modification; hormone therapy; improved; in vivo Model; innovation; malignant breast neoplasm; mouse model; next generation; non-genomic; novel; prognostic; receptor function; statistics; therapy development; therapy resistant; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The human estrogen receptor (ER) is a key transcription regulator in breast cancer biology. However the precise mechanism of ER action is not completely understood. Emerging evidence suggests that ER action is complex and requires functional interactions with coregulators. As a modulator of ER functions, coregulators are likely to play a role in breast cancer progression. There is a critical need to understand the role of ER coregulators in the initiation and progression of breast cancer and in the development of therapy resistance and metastasis. Our long term goal is to discover the role of ER coregulators in breast cancer progression and therapy resistance and to identify key ER coregulators that serve as alternative targets for current endocrine therapies. Our recent studies showed that PELP1 is a novel proto-oncogene that participates in ER genomic actions and nongenomic actions and its expression is deregulated in breast tumors. The objective of this application is to characterize the mechanisms by which ER coregulator PELP1 contributes to breast cancer progression, metastasis and to validate ER-PELP1 axis as a potential target for diagnosis and therapeutic intervention. Our central hypotheses are that ER coregulator PELP1 is a proto- oncogene, plays a critical role in the ER mediated chromatin modifications and cell cycle progression, its deregulation confer a growth advantage to breast epithelial cells and consequently, contribute towards malignant progression, metastasis and resistance to hormonal therapy. To investigate these hypotheses, in Aim 1, we will define the role of PELP1 in histone modifications and epigenetic code at the ER target genes. In aim 2, we will elucidate the mechanisms by which PELP1 promote E2 mediated cell proliferation, cell cycle progression and characterize the role of PELP1 in histone biosynthesis. In aim 3, we wil establish the mechanism and significance of PELP1-nongenomic signaling in ER therapy resistance. In aim4, we will determine the role of PELP1 in metastasis and evaluate its prognostic value in metastatic breast cancer. We will test these aims using molecular biology, proteomics, epigenetic and ChIP methodology and by using novel in vitro and in vivo models, and IHC studies using tumor arrays. Our proposed research is significant because of the novelty of the concepts involving PELP1 and findings from the proposed studies will define the role(s) of PLEP1 as a critical proto-oncogene of breast cancer progression by coupling ER with epigenetic modulators. In addition, this proposal establishes the role of ER-PELP1 axis in metastasis and hormonal therapy resistance and thus provide novel target for combination therapies to treat metastatic and advanced breast tumors. Understanding the key ER coregulators and their signal transduction mechanism will be a step forward for developing strategies for the next generation of advances in anti-estrogenic therapies. PUBLIC HEALTH RELEVANCE: The human estrogen receptor (ER) is a key regulator in breast cancer biology. Our proposed research is clinically significant as it will define the role(s) of ER coregulator PELP1 as a critical proto-oncogene of breast cancer progression. Further, our proposed studies establishes the role of ER-PELP1 axis in metastasis and hormonal resistance and thus provide a novel target for combination therapies to treat metastatic and advanced breast tumors.

描述（由申请人提供）：人类雌激素受体（ER）是乳腺癌生物学中的关键转录调节因子。然而，ER 作用的精确机制尚不完全清楚。新出现的证据表明，ER 作用很复杂，需要与核心调节器进行功能性相互作用。作为 ER 功能的调节剂，核心调节剂可能在乳腺癌进展中发挥作用。迫切需要了解 ER 共调节因子在乳腺癌发生和进展以及治疗耐药和转移发展中的作用。我们的长期目标是发现 ER 核心调节因子在乳腺癌进展和治疗耐药中的作用，并确定关键的 ER 核心调节因子作为当前内分泌治疗的替代靶点。我们最近的研究表明，PELP1是一种新型原癌基因，参与ER基因组作用和非基因组作用，并且其表达在乳腺肿瘤中失调。本申请的目的是表征 ER 核心调节因子 PELP1 促进乳腺癌进展、转移的机制，并验证 ER-PELP1 轴作为诊断和治疗干预的潜在靶点。我们的中心假设是，ER 核心调节因子 PELP1 是一种原癌基因，在 ER 介导的染色质修饰和细胞周期进展中发挥关键作用，其失调赋予乳腺上皮细胞生长优势，从而导致恶性进展、转移和对激素治疗的抵抗。为了研究这些假设，在目标 1 中，我们将定义 PELP1 在 ER 靶基因的组蛋白修饰和表观遗传密码中的作用。在目标 2 中，我们将阐明 PELP1 促进 E2 介导的细胞增殖、细胞周期进展的机制，并表征 PELP1 在组蛋白生物合成中的作用。在目标 3 中，我们将建立 PELP1 非基因组信号在 ER 治疗耐药中的机制和意义。在目标4中，我们将确定PELP1在转移中的作用并评估其在转移性乳腺癌中的预后价值。我们将使用分子生物学、蛋白质组学、表观遗传学和 ChIP 方法以及使用新型体外和体内模型以及使用肿瘤阵列的 IHC 研究来测试这些目标。我们提出的研究具有重要意义，因为涉及 PELP1 的概念新颖，并且拟议研究的结果将通过将 ER 与表观遗传调节剂偶联来定义 PLEP1 作为乳腺癌进展的关键原癌基因的作用。此外，该提案确立了 ER-PELP1 轴在转移和激素治疗抵抗中的作用，从而为治疗转移性和晚期乳腺肿瘤的联合疗法提供了新的靶点。了解关键的 ER 核心调节因子及其信号转导机制将有助于制定下一代抗雌激素治疗进展的策略。公共健康相关性：人类雌激素受体 (ER) 是乳腺癌生物学的关键调节因子。我们提出的研究具有临床意义，因为它将定义 ER 核心调节因子 PELP1 作为乳腺癌进展的关键原癌基因的作用。此外，我们提出的研究确立了 ER-PELP1 轴在转移和激素抵抗中的作用，从而为治疗转移性和晚期乳腺肿瘤的联合疗法提供了新的靶点。