PELP1, a Novel Regulator of Estrogen Receptor

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，内质网作用的确切机制尚不完全清楚。新出现的证据表明，内质网的作用是复杂的，需要与协同调节因子的功能相互作用。作为内质网功能的调节因子，共调节因子可能在乳腺癌的进展中发挥作用。迫切需要了解内质网共调节因子在乳腺癌的发生和发展以及治疗耐药和转移中的作用。我们的长期目标是发现雌激素受体共调节因子在乳腺癌进展和治疗耐药中的作用，并确定作为当前内分泌治疗替代靶点的关键雌激素受体共调节因子。我们最近的研究表明，PELP1是一种新型的原癌基因，参与内质网的基因组作用和非基因组作用，其在乳腺肿瘤中的表达不受调控。本应用的目的是表征ER共调节因子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。我们的主要假设是，内质网共调节因子PELP1是一种原癌基因，在内质网介导的染色质修饰和细胞周期进程中起着关键作用，其失调赋予乳腺上皮细胞生长优势，从而促进恶性进展、转移和对激素治疗的抵抗。为了研究这些假设，在Aim 1中，我们将定义PELP1在内质网靶基因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、细胞周期进程的机制，并表征PELP1在组蛋白生物合成中的作用。在aim 3中，我们将建立pelp1 -非基因组信号在内质网治疗耐药中的机制和意义。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ChIP方法，并使用新的体外和体内模型，以及使用肿瘤阵列的免疫组化研究来测试这些目标。我们提出的研究是重要的，因为涉及PELP1的概念是新颖的，并且来自拟议研究的结果将通过内质网与表观遗传调节剂的偶联来确定PLEP1作为乳腺癌进展的关键原癌基因的作用。此外，本研究建立了ER-PELP1轴在转移和激素治疗抵抗中的作用，从而为联合治疗转移性和晚期乳腺肿瘤提供了新的靶点。了解关键的内质网共调节因子及其信号转导机制将是下一代抗雌激素治疗发展策略的一步。公共卫生相关性：人类雌激素受体（ER）是乳腺癌生物学中的关键调节因子。我们提出的研究具有临床意义，因为它将确定ER共调节因子PELP1作为乳腺癌进展的关键原癌基因的作用。此外，我们提出的研究确定了ER-PELP1轴在转移和激素抵抗中的作用，从而为转移性和晚期乳腺肿瘤的联合治疗提供了新的靶点。

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.