Epigenetic Regulation of Breast Cancer Progression by the Proto-oncogene PELP1

原癌基因 PELP1 对乳腺癌进展的表观遗传调控

• 批准号: 8526105
• 负责人: Monica Mann
• 金额: $ 2.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526105
• 关键词: Affect; Agar; Antibodies; Arginine; Aromatase Inhibitors; Bioinformatics; Biological Assay; Cancer Biology; Cancer Etiology; Cancer Patient; Cells; Cessation of life; ChIP-seq; Code; Complex; Disease-Free Survival; Enzymes; Epigenetic Process; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Event; Exhibits; Figs - dietary; Gene Activation; Gene Targeting; Genes; Genetic Transcription; Genome; Histone H3; Histones; Hormonal; Human; Immunohistochemistry; Luciferases; Malignant Neoplasms; Mentors; Methylation; Migration Assay; Modeling; Modification; Molecular; Mus; Nature; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Prognostic Marker; Proto-Oncogenes; Quantitative Reverse Transcriptase PCR; RNA Sequences; RNA methylation; Receptor Activation; Receptor Gene; Regulation; Reporter Genes; Research; Research Personnel; Research Training; Resistance; Role; Small Interfering RNA; Tamoxifen; Testing; Therapeutic; Tissue Microarray; Tissues; Tumor Tissue; Woman; Work; Xenograft procedure; base; career; clinically significant; coactivator-associated arginine methyltransferase 1; design; epigenome; histone methyltransferase; histone modification; hormone related cancer; hormone therapy; improved; in vitro activity; inhibitor/antagonist; malignant breast neoplasm; neoplastic cell; novel; overexpression; promoter; public health relevance; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death in women. Estrogen and its target estrogen receptor alpha (ER¿), a master transcriptional regulator, are implicated in the initiation and progression of breast cancer. Endocrine therapies using tamoxifen and aromatase inhibitors substantially improve disease- free survival, however, initial or acquired resistance frequently occurs. While the molecular mechanism by which tumor cells modulate epigenetic changes at ER¿ target genes remains elusive, the deregulation of epigenetic modifiers may contribute to oncogenesis and therapy resistance. As a consequence, there is a critical need to understand the molecular mechanism(s) by which deregulation of epigenetic changes occurs during breast cancer progression. The transcriptional functions of ER¿ are influenced by several coactivators, including PELP1 and CARM1, that associate with histone modifying activities. PELP1 is an ER¿ coregulator and proto-oncogene with aberrant expression in hormone-related cancers and is an independent prognostic indicator of decreased survival in breast cancer patients. The molecular mechanism by which PELP1 promotes oncogenesis is not completely understood. My preliminary findings suggest that (1) PELP1 has the ability to recognize arginine di-methyl modified histone H3; (2) PELP1 interacts with the histone modifying enzyme CARM1; (3) PELP1 status affects CARM1 recruitment to ER¿ target genes and (4) PELP1 knockdown affects arginine methylation at ER¿ target genes. Based on these strong preliminary findings, I hypothesize that PELP1 interactions with CARM1 are crucial for PELP1 oncogenic functions and the PELP1-CARM1 axis determines the arginine methylation code at the ER¿ target genes leading to breast cancer progression. The objective of this proposal is to characterize the functional interaction of the PELP1 and CARM1 complex and determine the mechanism of epigenetic regulation of breast cancer progression by identifying the target genes and pathways. I will test my hypothesis using two specific aims. In Aim 1, I will test the significance of the PELP1-CARM1 axis in breast cancer by histone methyltransferase, reporter gene, proliferation and migration assays as well as a tumor tissue array. In Aim 2, I will determine the role of PELP1 regulation of the epigenome via arginine methylation by RNA- and ChIP-sequencing as well as ChIP, immunohistochemistry and qRTPCR analysis of murine tissues. Understanding the mechanism by which PELP1 modulates epigenetic changes and the reversible nature of these modifications provides a unique therapeutic opportunity to design novel drugs for treating hormonal cancers.

描述（由申请人提供）：乳腺癌是女性癌症死亡的第二大原因。雌激素及其靶向雌激素受体α（ER <$），一种主要的转录调节因子，与乳腺癌的发生和发展有关。 使用他莫昔芬和芳香化酶抑制剂的内分泌疗法显著改善了无病生存率，然而，经常发生初始或获得性耐药。虽然肿瘤细胞调节ER靶基因的表观遗传变化的分子机制仍然难以捉摸，但表观遗传修饰剂的失调可能有助于肿瘤发生和治疗抗性。因此，迫切需要了解乳腺癌进展过程中表观遗传变化失调的分子机制。ER <$的转录功能受到几种辅激活因子的影响，包括PELP 1和CARM 1，它们与组蛋白修饰活性相关。PELP 1是一个ER？在乳腺癌相关的癌症中具有异常表达的辅助调节因子和原癌基因，并且是乳腺癌患者中降低的存活率的独立预后指标。PELP 1促进肿瘤发生的分子机制尚不完全清楚。我的初步研究结果表明：（1）PELP 1具有识别精氨酸二甲基修饰的组蛋白H3的能力;（2）PELP 1与组蛋白修饰酶CARM 1相互作用;（3）PELP 1状态影响CARM 1向ER <$靶基因的募集;（4）PELP 1敲低影响ER <$靶基因的精氨酸甲基化。基于这些强有力的初步发现，我假设PELP 1与CARM 1的相互作用对于PELP 1致癌功能至关重要，并且PELP 1-CARM 1轴决定了ER ²靶基因的精氨酸甲基化密码，导致乳腺癌进展。该提案的目的是表征PELP 1和CARM 1复合物的功能相互作用，并通过鉴定靶基因和途径来确定乳腺癌进展的表观遗传调控机制。我将用两个具体目标来检验我的假设。目的1：通过组蛋白甲基转移酶、报告基因、增殖和迁移实验以及肿瘤组织芯片检测PELP 1-CARM 1轴在乳腺癌中的意义。在目标2中，我将 通过RNA和ChIP测序以及ChIP、免疫组织化学和小鼠组织的qRTPCR分析，确定PELP 1通过精氨酸甲基化调节表观基因组的作用。了解PELP 1调节表观遗传变化的机制以及这些修饰的可逆性为设计治疗激素癌症的新药提供了独特的治疗机会。