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）是乳腺癌生物学的关键转录调节剂。但是，尚不完全了解ER作用的确切机制。新兴的证据表明，ER的作用很复杂，需要与核控器的功能相互作用。作为ER功能的调节剂，核心节可能在乳腺癌进展中起作用。迫切需要了解ER组合剂在乳腺癌的启动和进展以及在耐药性和转移发展方面的作用。我们的长期目标是发现ER组分群在乳腺癌进展和耐药性中的作用，并确定作为当前内分泌疗法的替代靶标的关键ER核心调节剂。我们最近的研究表明，PELP1是一种新型的原型癌基因，它参与ER基因组作用和非基因组作用，其表达在乳腺肿瘤中受到了管制。该应用的目的是表征ER核心测量器PELP1有助于乳腺癌进展，转移并验证ER-PELP1轴的机制，以此作为诊断和治疗干预的潜在目标。我们的中心假设是ER核心凝管PELP1是一种原型癌基因，在ER介导的染色质修饰和细胞周期进展中起着至关重要的作用，其放松管制给乳腺上皮细胞带来了生长优势，因此有助于恶性进展，转移和对荷尔蒙治疗的抵抗力。为了研究这些假设，在AIM 1中，我们将定义PELP1在ER靶基因对组蛋白修饰和表观遗传密码中的作用。在AIM 2中，我们将阐明PELP1促进E2介导的细胞增殖，细胞周期进程并表征PELP1在组蛋白生物合成中的作用的机制。在AIM 3中，我们将建立PELP1-核信号传导在ER治疗耐药性中的机制和意义。在AIM4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，表观遗传学和芯片方法以及使用新型体外和体内模型以及使用肿瘤阵列进行IHC研究来测试这些目标。我们提出的研究之所以重要，是因为涉及PELP1的概念的新颖性和拟议研究的发现将将PLEP1的作用定义为通过与表观遗传调节剂耦合ER，将PLEP1的作用定义为乳腺癌进展的关键原始癌基因。此外，该提案确定了ER-PELP1轴在转移和荷尔蒙疗法耐药性中的作用，因此为治疗转移性和晚期乳腺肿瘤的联合疗法提供了新的靶标。了解关键的ER核心调节剂及其信号转导机制将是开发抗雌激素疗法进步的策略的一步。公共卫生相关性：人类雌激素受体（ER）是乳腺癌生物学的关键调节剂。我们提出的研究在临床上具有重要意义，因为它将定义ER核心测量剂PELP1的作用是乳腺癌进展的关键原始癌基因。此外，我们提出的研究确定了ER-PELP1轴在转移和激素耐药性中的作用，因此为治疗转移性和晚期乳腺肿瘤的组合疗法提供了新的靶标。