MOLECULAR/CYTOGENETICS--ESTROGEN INDUCED RENAL NEOPLASIA

描述：（申请人摘要）绝大多数流行病学 数据表明，人类乳腺癌和子宫内膜癌的主要危险因素 癌症与女性性激素有关 雌激素（ES）是一种 与这些和其他乳腺癌相关癌症的病因有关， 妇女 E诱导的肿瘤的研究涉及基本的细胞和 Es参与靶细胞致癌过程的分子机制 没有其他外源性因子存在的组织。 最近的调查结果， 申请人及其同事已经指出， 这些激素是负责发展E-诱导肾 仓鼠的癌症 这是一个明显的背离大多数 之前使用该模型的研究。 申请人及其同事建议 E-驱动的连续多步骤方案在E-诱导的肿瘤发生中的作用 仓鼠肾细胞毒性;修复性细胞增殖; 非整倍体;基因组（染色体）不稳定性;不适当的细胞周期 基因、原癌基因和抑制基因表达;和基因扩增。 为了进一步测试E致癌作用的多步骤方案， 根据这一模式，申请人提出了三个具体目标。 目标1：确定 是否E-反应基因在早期升高或过度表达， 相对于正常肾脏，原发性肾脏肿瘤与 获得或丢失的染色体，并评估观察到的 染色体畸变（染色单体和染色体断裂）是非随机的。 目的2：探讨雌激素受体（ER）在乳腺癌发生发展中的作用， 诱导表达和E-诱导表达中可能的突变和变体 肾脏肿瘤与正常肾脏相比。 ER中的这些改变可能 有助于早期肿瘤病变和肿瘤病灶的生长优势。 目的3是确定E在G1期进展调节中的作用 在E诱导的致癌过程中。 细胞增殖失控， 通常由于细胞周期G1期进展的失调， 导致恶性肿瘤的重要机制。 这些研究 仓鼠肾脏中的电子致癌作用将为以下方面提供重要的见解： 其它E诱导的癌症系统（例如，乳腺和子宫肿瘤模型）和 有助于我们了解E相关的病因 人类癌症

DESCRIPTION: (Applicant's Abstract) The vast majority of epidemiological data indicate that major risk factors for human breast and endometrial cancer involve female sex hormones. Estrogens (Es) have been notably implicated in the etiology of these and other hormone-associated cancers in women. The study of E-induced neoplasms addresses the basic cellular and molecular mechanisms involving Es in carcinogenic processes in target tissues where no other exogenous agent is present. Recent findings by the applicant and colleagues have indicated that the inherent estrogenicity of these hormones is responsible for the development of E-induced renal carcinomas in hamsters. This represents a marked departure from most of the previous studies using this model. The applicant and colleagues propose an E-driven sequential multi-step scheme for E-induced carcinogenesis in the hamster kidney which involves cytotoxicity; reparative cell proliferation; aneuploidy; genomic (chromosomal) instability; inappropriate cell cycle gene, protooncogene, and suppressor gene expression; and gene amplification. To test further aspects of the multi-step scheme of E carcinogenesis in this model, the applicant proposes three specific aims. Aim 1 is to determine whether the E-responsive genes which are elevated or overexpressed in early primary renal tumors relative to normal kidney are associated with chromosomes that are either gained or lost, and assess whether the observed chromosomal aberrations (chromatid and chromosome breaks) are nonrandom. Aim 2 is to examine the role of estrogen receptor (ER), including its induced expression and possible mutations and variants in the E-induced renal tumor compared to normal kidney. These alterations in ER may contribute to growth advantages of early tumorous lesions and tumor foci. Aim 3 is to determine the role of E in the regulation of G1 progression during E-induced carcinogenesis. Uncontrolled cell proliferation, frequently due to dysregulation of G1 progression of the cell cycle, is an important mechanism leading to malignancy. These studies of E-carcinogenesis in the hamster kidney will provide important insights for other E-induced cancer systems (e.g., breast and uterine tumor models) and contribute importantly to our understanding of the etiology of E-associated human cancers.