ASC ? A NOVEL TUMOR SUPPRESSOR GENE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 凋亡相关的斑点样蛋白（Apoptosis-associated speck-like protein，ASC）是一种衔接蛋白，其含有半胱天冬酶募集结构域（caspase recruitment domain，ASC），参与先天免疫调节和凋亡。 最近人们认识到与癌症的密切联系，68%的乳腺癌患者携带ASC基因。 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作为一种肿瘤抑制基因在乳腺上皮细胞中通过阻断IKK复合物的异常NF-κ B活性发挥作用。 ASC的沉默为肿瘤细胞提供了一种逃避增殖和凋亡的良好平衡控制的机制，从而导致癌症的发展。 本研究的目的是阐明ASC在乳腺癌中的功能，并确定ASC表达缺失促进乳腺癌的机制。 为实现这一目标，我们提出以下具体目标： 1.）的人。为了确定ASC沉默促进乳腺癌的分子机制： 1A.）确定ASC沉默对乳腺癌细胞增殖的影响; 1B.）评价ASC钝化后乳腺癌细胞的凋亡情况; 1C.）探讨ASC调节乳腺癌细胞侵袭力的机制; 2.）探讨ASC在乳腺癌发生、发展中的作用。 我们的研究设计为（1）通过将异位ASC稳定转染到ASC缺陷型乳腺癌细胞系中来恢复ASC表达，以及（2）通过在ASC正常乳腺癌细胞系中进行RNA干扰来敲低ASC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人。 ASC沉默发生在大多数癌中。 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.