Roles of SRC-3 in Development and Disease

SRC-3 在发育和疾病中的作用

• 批准号: 8477019
• 负责人: JIANMING XU
• 金额: $ 29.34万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477019
• 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 Targeting; 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 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; prostate cancer cell; prostate carcinogenesis; 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.

描述（由申请人提供）：p160类固醇受体辅激活因子（SRC）家族的三个成员增强由核受体和某些其他转录因子介导的基因转录。在上一个资助周期中，我们通过使用遗传小鼠模型广泛研究了这些共激活因子的体内功能。我们已发表的工作已经牢固地确立了SRC家族在许多生理和病理过程中的重要性和必要的多效性作用。我们发现SRC家族成员调节发育、躯体生长、血管保护、生殖和内分泌功能。此外，SRC家族成员促进乳腺癌和前列腺癌的发生和进展。特别值得注意的是，小鼠中SRC 3的基因消融抑制了前列腺癌的进展，将肿瘤抑制在分化良好的状态。虽然SRC 3在基底细胞（BC）中表达，但在正常外分泌腔上皮细胞（ELEC）中不表达，但其在晚期前列腺肿瘤中过表达。根据前列腺上皮稳态的干细胞（SC）概念和我们的初步研究，我们假设SRC 3在基底SC、中间细胞（IMC）和癌症干细胞（CSC）中表达; SRC 3沉默是ELEC分化所需的;并且持续SRC 3表达是CSC以及雄激素非依赖性肿瘤细胞偏离和维持所需的。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SRC 3在每种前列腺上皮细胞类型中的表达模式及其在维持成年动物前列腺上皮稳态中的决定性作用。我们将研究SRC 3是否在前列腺上皮的SC、IMC、CSC和神经内分泌细胞（NECs）中表达，以及ELEC中SRC 3的异位表达是否会影响增殖、分化和转化。第二个目的是定义SRC 3在前列腺癌发生和进展期间CSC的衍生和维持中的作用。我们将开发一种可诱导的基因靶向系统，以特异性地将推定的干细胞/前体细胞谱系中的SRC 3等位基因固定，以研究该细胞谱系中的SRC 3缺陷是否会抑制CSC形成和前列腺癌进展。第三个目的是研究前列腺癌细胞中SRC 3的表达是否是SRC 3阴性肿瘤细胞中SRC 3诱导的结果，并确定这种SRC 3诱导是否促进前列腺癌进展。我们将有条件地敲除ELEC谱系中的SRC 3，并测试这是否会阻止SRC 3在前列腺肿瘤细胞中的表达和前列腺癌的进展。这些研究将阐明SRC 3阳性前列腺癌细胞的细胞系特异性起源以及SRC 3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SRC 3是前列腺癌治疗的细胞系特异性和肿瘤阶段特异性靶标。