Roles of SRC-3 in Development and Disease

SRC-3 在发育和疾病中的作用

• 批准号: 8305166
• 负责人: JIANMING XU
• 金额: $ 30.7万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305166
• 关键词: Ablation; Address; Adenocarcinoma; Adenocarcinoma Cell; Adult; Affect; Agreement; Alleles; Androgen Receptor; Androgens; Apoptosis; Basal Cell; Binding; Birth; Blood Vessels; Cell Differentiation process; Cell Lineage; Cell Nucleus; Cell Proliferation; Cell model; Cells; Chimeric Proteins; Cyclin D1; Cytoplasm; Derivation procedure; Development; Diagnostic; Diagnostic Neoplasm Staging; Disease; Down-Regulation; Drug Delivery Systems; Endocrine; Endocrinology; Environment; Epithelial; Epithelial Cells; Epithelium; Estrogens; Exhibits; FGR gene; Failure; Family; Family member; Female; Funding; Galactosidase; Gene Targeting; Genes; Genetic; Genetic Transcription; Growth; Health; Heterogeneity; Histologic; Homeostasis; Hormones; Human; Hyperplasia; Immunohistochemistry; Infertility; Inherited; Insulin-Like Growth Factor I; Knock-in Mouse; Knock-out; Knowledge; Label; Letters; MMP2 gene; MMP9 gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Modeling; Molecular; Molecular Target; Mus; Mutant Strains Mice; NCOA3 gene; Neoplasm Metastasis; Neuroendocrine Cell; Nuclear Receptors; Oncogene Proteins; Oncogenes; Organ; Paper; Pattern; Phenotype; Physiological; Play; Population; Process; Progress Reports; Prostate; Prostatic; Prostatic Epithelium; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Puberty; Publications; Publishing; Purkinje Cells; Rattus; Reporter; Reproduction; Research; Resistance; Role; Signal Pathway; Simian virus 40; Solid; Spermiogenesis; Staging; Stem cells; Steroid Receptors; Stratum Basale; System; Tamoxifen; Testing; Thyroid Hormone Resistance Syndrome; Transgenes; Transgenic Mice; Transgenic Organisms; Tumor stage; Work; cancer cell; cancer initiation; cancer stem cell; cancer therapy; carcinogenesis; cell type; chemical carcinogen; deprivation; design; human disease; in vivo; male; malignant breast neoplasm; mammary gland development; mature animal; member; men; mouse model; neoplastic cell; novel; overexpression; precursor cell; prevent; probasin; progenitor; programs; promoter; recombinase; reproductive function; selective expression; self-renewal; stem; stem cell differentiation; stem cell population; steroid hormone; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The three members of the p160 steroid receptor coactivator (SRC) family enhance gene transcription mediated by nuclear receptors and certain other transcription factors. During the last funding cycle, we extensively studied the in vivo functions of these coactivators by using genetic mouse models. Our published works have firmly established the importance and essential pleiotropic roles of the SRC family in many physiological and pathogenetic processes. We found that SRC family members regulate development, somatic growth, vascular protection, reproduction and endocrine function. Furthermore, SRC family members promote breast and prostate cancer initiation and progression. Of particular note, genetic ablation of SRC3 in mice inhibits prostate cancer progression, arresting tumors in a well-differentiated state. While SRC3 is expressed in the basal cells (BCs) but not expressed in the normal exocrine luminal epithelial cells (ELECs), it is overexpressed in the advanced prostate tumors. In line with the stem cell (SC) concept for prostate epithelial homeostasis and our preliminary studies, we hypothesize that SRC3 is expressed in the basal SCs, intermediate cells (IMCs) and cancer stem cells (CSCs); SRC3 silencing is required for ELEC differentiation; and persistant SRC3 expression is required for deviation and maintenance of CSCs as well as androgen-independent tumor cells. To test our hypothesis, we will pursue three specific aims. The first aim is to define the SRC3 expression pattern in each cell type of prostate epithelium and its determinant role in maintenance of prostate epithelial homeostasis in adult animal. We will address if SRC3 is expressed in SCs, IMCs, CSCs and neuroendocrine cells (NECs) of the prostate epithelium, and whether ectopic SRC3 expression in ELECs will affect proliferation, differentiation and transformation. The second aim is to define the role of SRC3 in derivation and maintenance of CSCs during prostate cancer initiation and progression. We will develop an inducible gene targeting system to specifically inactivate floxed SRC3 alleles in the putative stem/precursor cell lineage to investigate if SRC3 deficiency in this cell lineage will inhibit CSC formation and prostate cancer progression. The third aim is to investigate whether SRC3 expression in prostate cancer cells results from SRC3 induction in SRC3-negative tumor cells and to determine if this SRC3 induction promotes prostate cancer progression. We will conditionally knock out SRC3 in the ELEC lineage and test if this will prevent SRC3 expression in prostate tumor cells and prostate cancer progression. These studies will elucidate the cell lineage-specific origin of SRC3-positive prostate cancer cells as well as the cell type-specific role of the SRC3 proto- oncoprotein in prostate cancer progression. The knowledge to be obtained from these proposed studies may suggest SRC3 as a cell lineage-specific and tumor stage-specific target for prostate cancer treatment. PUBLIC HEALTH RELEVANCE: The male hormone androgen-promoted prostate cancer and prostatis are major health problems for men. Since the steroid receptor coactivator 3 (SRC3) enhances androgen actions, it may be responsible for these hormonally promoted diseases. This research program is designed to understand the physiological and pathogenetic roles and mechanisms of SRC3 in prostatic epithelial homeostasis, function and cancer formation in adult and to test SRC3 as a molecular target for inhibition of prostate cancer in mouse models. These studies will help to identify SRC3-positive cancer stem cells, potential diagnostic markers and drug targets for human prostate cancer treatment.

描述(申请人提供)：p160类固醇受体辅活化子(SRC)家族的三个成员通过核受体和某些其他转录因子促进基因转录。在上一个资助周期中，我们通过遗传小鼠模型广泛研究了这些共激活子在体内的功能。我们发表的研究成果已经确立了SRC家族在许多生理和致病过程中的重要性和基本的多效性作用。我们发现SRC家族成员对发育、躯体生长、血管保护、生殖和内分泌功能具有调节作用。此外，SRC家族成员促进乳腺癌和前列腺癌的发生和发展。特别值得注意的是，在小鼠中进行SRC3的基因消融可以抑制前列腺癌的发展，阻止处于高分化状态的肿瘤。SRC3在基底细胞(BCS)中表达，在正常外分泌腔上皮细胞(ELECs)中不表达，在进展期前列腺癌中高表达。根据干细胞(SC)对前列腺上皮动态平衡的概念和我们的初步研究，我们假设SRC3在基础干细胞、中间细胞(IMCs)和癌症干细胞(CSCs)中表达；SRC3沉默是Elec分化所必需的；持续的SRC3表达是CSCs偏离和维持以及雄激素非依赖性肿瘤细胞所必需的。为了验证我们的假设，我们将追求三个具体目标。第一个目的是确定SRC3在每种细胞类型的前列腺上皮中的表达模式及其在维持成年动物前列腺上皮内环境平衡中的决定作用。我们将讨论SRC3是否在前列腺上皮的SCs、IMCs、CSCs和神经内分泌细胞(NECs)中表达，以及在ELECs中的异位表达是否会影响增殖、分化和转化。第二个目的是确定SRC3在前列腺癌发生和发展过程中CSCs的产生和维持中的作用。我们将开发一种可诱导的基因打靶系统，以特异性地灭活假定的干细胞/前体细胞谱系中的SRC3等位基因，以研究该细胞谱系中SRC3缺陷是否会抑制CSC的形成和前列腺癌的进展。第三个目的是研究SRC3在前列腺癌细胞中的表达是否源于SRC3对SRC3阴性肿瘤细胞的诱导，并确定这种SRC3诱导是否促进前列腺癌的进展。我们将有条件地敲除ELEC谱系中的SRC3，并测试这是否会阻止前列腺肿瘤细胞中SRC3的表达和前列腺癌的进展。这些研究将阐明SRC3阳性前列腺癌细胞系特异性起源以及SRC3原癌蛋白在前列腺癌进展中的细胞类型特异性作用。从这些拟议的研究中获得的知识可能表明SRC3是前列腺癌治疗的细胞系特异性和肿瘤阶段特异性靶点。公共卫生相关性：男性荷尔蒙、雄激素促进的前列腺癌和前列腺癌是男性的主要健康问题。由于类固醇受体辅活化子3(SRC3)增强了雄激素的作用，它可能与这些由激素促进的疾病有关。本研究旨在了解SRC3在成人前列腺上皮细胞内稳态、功能和肿瘤形成中的生理和病理作用及机制，并在小鼠模型中测试SRC3作为抑制前列腺癌的分子靶点。这些研究将有助于确定SRC3阳性的癌症干细胞、潜在的诊断标记和人类前列腺癌治疗的药物靶点。