ASC ? A NOVEL TUMOR SUPPRESSOR GENE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 凋亡相关的SPECK样蛋白含有半胱氨酸天冬氨酸氨基转移酶招募结构域(ASC)，是一种适配蛋白，与天然免疫调节和细胞凋亡有关。最近人们认识到与癌症有很强的联系，68%的乳腺癌患者ASC基因失活。ASC通过诱导支持肿瘤细胞增殖、侵袭和存活的基因来调节与乳腺肿瘤发生密切相关的转录因子的活性。然而，ASC在乳腺癌中的直接作用仍然难以捉摸，需要确定。 我们的假设是，ASC通过阻断IKK复合体中异常的核因子-kappaB活性，在乳腺上皮细胞中发挥肿瘤抑制基因的作用。ASC的沉默为肿瘤细胞逃避增殖和凋亡的平衡控制提供了一种机制，从而导致癌症的发展。 本研究的目的是阐明ASC在乳腺癌中的作用，并确定ASC表达缺失促进乳腺癌发生的机制。为了达到这一目的，我们提出了以下具体目标： 1)为了确定ASC沉默促进乳腺癌的分子机制： (1A.)目的：研究ASC沉默对乳腺癌细胞增殖的影响； 1B.)检测ASC钝化的乳腺癌细胞的凋亡情况； 1C。)确定ASC调节乳腺癌细胞侵袭力的机制； 2.)目的：探讨ASC在体内乳腺癌发生发展中的作用。 我们的研究旨在(1)通过稳定地将异位ASC导入ASC缺陷的乳腺癌细胞系来恢复ASC的表达；(2)通过RNA干扰在ASC熟练的乳腺癌细胞系中下调ASC的表达，以模拟ASC沉默。如果要开发更有效的治疗方案，则有必要对与乳腺癌易感性相关的基因进行表征。 这项研究支持了我们的长期目标，即了解乳腺肿瘤发生的分子机制，并确定和表征乳腺癌预防和治疗的候选对象。ASC沉默发生在大多数癌症中。因此，我们预计，这项研究的结果不仅与更好地了解乳腺癌的进展有关，而且对其他几种类型的癌症也有重要意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adapter protein, which is implicated in innate immune regulation and apoptosis. A strong link to cancer has been recently recognized, when 68% of breast cancers inactivate the ASC gene. ASC modulates activity of transcription factors that are closely linked to mammary tumorigenesis by inducing genes that support proliferation, invasiveness and survival of tumor cells. However, the direct role of ASC in breast cancer is still elusive and needs to be determined. Our hypothesis is that ASC functions as a tumor suppressor gene in mammary epithelial cells by blocking aberrant NF-kappaB activity at the IKK complex. Silencing of ASC provides one mechanism for tumor cells to escape the well-balanced control of proliferation and apoptosis, resulting in the development of cancer. The objective of this study is to elucidate the function of ASC in breast cancer and to determine the mechanism by which loss of ASC expression promotes breast cancer. To achieve this purpose, we propose the following specific aims: 1.) To determine the molecular mechanism by which ASC silencing promotes breast cancer: 1A.) To determine the effect of ASC silencing on proliferation of breast cancer cells; 1B.) To evaluate apoptosis of breast cancer cells in which ASC has been blunted; 1C.) To determine the mechanism by which ASC may regulate invasiveness of breast cancer cells; 2.) To evaluate the role of ASC in in vivo breast cancer initiation and progression. Our study is designed (1) to restore ASC expression by stable transfection of ectopic ASC into ASC deficient breast cancer cell lines, and (2) to knock-down expression of ASC by RNA interference in ASC proficient breast cancer cell lines to simulate ASC silencing. Characterization of genes associated with breast cancer susceptibility is necessary, if more efficient treatment options are to be developed. This study supports our long-term goal of understanding the molecular mechanisms of mammary tumorigenesis and to identify and characterize candidates for breast cancer prevention and therapy. ASC silencing occurs in most carcinomas. Therefore, we anticipate that results from this study are not only relevant for better understanding the progression of mammary carcinomas, but will be significant for several other types of carcinomas, as well.