MOLECULAR/CYTOGENETICS--ESTROGEN INDUCED RENAL NEOPLASIA

描述：(申请者摘要)绝大多数流行病学 数据表明，人类乳房和子宫内膜的主要危险因素 癌症与女性性激素有关。值得注意的是，雌激素 与这些癌症和其他激素相关癌症的病因学有关 女人。E诱导肿瘤的研究涉及基本的细胞和 ES参与靶区致癌过程的分子机制 不存在其他外源性病原体的组织。世界银行的最新发现 申请者和同事们已经指出，雌激素的固有活性 这些激素参与了E诱导的肾脏的形成 仓鼠的癌症。这代表着与大多数 之前的研究使用了这个模型。申请者和同事提出了一个 E驱动的序贯多步方案用于E诱导的小鼠肿瘤的致癌 涉及细胞毒性的仓鼠肾脏；修复性细胞增殖； 非整倍体；基因组(染色体)不稳定；不适当的细胞周期 基因、原癌基因和抑癌基因的表达；以及基因扩增。 为了测试E致癌的多步骤方案的进一步方面 根据这一模式，申请人提出了三个具体目标。目标1是确定 早期表达上调或过度表达的E反应基因 相对于正常肾脏的原发肾脏肿瘤与 获得或丢失的染色体，并评估观察到的 染色体异常(染色单体和染色体断裂)是非随机的。 目的2是研究雌激素受体(ER)的作用，包括其 E诱导表达及可能的突变和变异体 肾肿瘤与正常肾比较。内质网的这些变化可能 有助于早期肿瘤病变和肿瘤灶的生长优势。 目标3是确定E在调节G1进程中的作用 在E诱导的致癌过程中。不受控制的细胞增殖， 通常是由于细胞周期的G1期进程失调，是一种 导致恶变的重要机制。这些研究是关于 仓鼠肾脏的E-癌发生将为 其他E诱发的癌症系统(例如，乳腺和子宫肿瘤模型)和 对我们理解E相关的病因有重要意义 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.