Molecular biomarkers of selenium chemoprevention

描述（由申请人提供）：先前的人体试验， 酵母表明，补硒显著降低发病率， 肺癌、结肠癌和前列腺癌。一项利用癌症的干预试验 作为终点的发病率需要很长时间才能完成，并且成本非常高。 因此，需要替代中间终点或生物标志物来评估 干预的有效性。我们在不久的将来的目标是计划一个 乳腺试验;一种可行的方法将是使用硒反应生物标志物 与硒化学预防的分子机制有关。 MCF 10AT和SUM-190 PT人乳腺细胞系将用于拟定的研究。 research.在移植后，MCF 10AT细胞能够发育成 概括人类增殖性淋巴瘤病理学的异型增生谱 乳腺疾病因此，该细胞系提供了一个理想的范例， 硒对高危病变的化学预防。SUM-190 PT细胞系，在 另一方面，表现出两个已知的乳腺癌基因的扩增和过度表达， 癌基因：erbB 2和细胞周期蛋白D1。它有一种基因型， 接近人类乳腺癌的水平。Aim 1将使用Affyssin基因芯片， 在体外鉴定人乳腺细胞中硒响应性生物标志物 系统基因表达的时间模式与 具有独特生物学结果的变化将提供重要的见解， 硒化学预防的分子机制。的调制 基因产物将通过半定量RT-PCR和/或Western blot进行确认。 分析.目的2：探讨GADD 153在人肝癌细胞中的功能意义。 硒控制细胞增殖和诱导细胞凋亡。这是一 在此基础上进行后续机制研究。目标3将验证 人类乳腺细胞中最敏感的生物标志物的表达 使用SCID小鼠的异种移植物模型。伴随研究的目的是 测定硒抑制肿瘤病理进展的能力， 异种移植（非典型导管增生至导管原位癌至浸润性 癌）。研究的化学预防部分是一个组成部分， 生物标志物项目，因为它是当务之急，以评估生物 生物标志物作为乳腺癌预后指标的相关性 保护目的4研究硒对小鼠的生物学效应， 治疗大鼠乳腺癌前病变的分子生物学 致癌物质我们的目标是扩大我们对 早期转化细胞的克隆抑制在硒保护中的作用 癌

DESCRIPTION (provided by applicant): A previous human trial with selenized yeast showed that selenium supplementation significantly reduced the incidence of lung, colon and prostate cancers. An intervention trial using cancer morbidity as the endpoint takes a long time to complete and is very costly. Surrogate intermediate endpoints or biomarkers are therefore needed to evaluate the efficacy of intervention. Our goal in the near future is to plan for a breast trial; a viable approach will be to use selenium-responsive biomarkers which are associated with the molecular mechanism of selenium chemoprevention. The MCF10AT and SUM-190PT human breast cell lines will be used for the proposed research. Upon transplantation, the MCF 10AT cells are able to develop a spectrum of dysplasia that recapitulate the pathology of human proliferative breast disease. Thus this cell line provides an ideal paradigm for studying selenium chemoprevention of high-risk lesions. The SUM-190PT cell line, on the other hand, exhibits amplification and over-expression of two known breast cancer oncogenes: erbB2 and cyclin D1. It harbors a genotype which is very close to that of human breast cancer. Aim 1 will use the Affymetrix GeneChip to identify selenium-responsive biomarkers in human breast cells in an in vitro system. A detailed correlation between the temporal pattern of gene expression changes with distinctive biological outcome would provide important insight into the molecular mechanism of selenium chemoprevention. The modulation of gene products will be confirmed by semi-quantitative RT-PCR and/or Western analysis. Aim 2 will investigate the functional significance of GADD153 in selenium control of cell proliferation and induction of apoptosis. This is a follow-up mechanism study based on our preliminary finding. Aim 3 will verify the expression of the most sensitive biomarkers in a human breast cell xenograft model using SCID mice. Companion studies will be designed to determine the ability of selenium to inhibit the pathologic progression of the xenograft (atypical ductal hyperplasia to ductal carcinoma in situ to invasive carcinoma). The chemoprevention component of the research is an integral part of the biomarker project because it is imperative to assess the biological relevance of the biomarkers as prognostic indicators of breast cancer protection. Aim 4 will study the effect of selenium on the biology and molecular biology of premalignant lesions in the mammary gland of rats treated with a carcinogen. The goal is to broaden our understanding of the significance of clonal suppression of early transformed cells in selenium protection of cancer.