Tumor suppressor adenomatous polyposis coli and breast carcinogenesis

抑癌性腺瘤性结肠息肉病与乳腺癌发生

• 批准号: 7234812
• 负责人: SATYA NARAYAN
• 金额: $ 27.63万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7234812
• 关键词: Tumor; suppressor; adenomatous; polyposis; coli

DESCRIPTION (provided by applicant): Our overall goal is to determine the role of the adenomatous polyposis coli (APC) gene in DNA damage-induced DNA repair activity and breast carcinogenesis. Down-regulation of APC is a predominant phenomenon in breast cancer, but neither its role in this disease nor the molecular alteration(s) underlying carcinogenesis in normal breast epithelial cells have been characterized. In the past, the role of mutated APC has been investigated in various cancers. In our studies, we propose a highly novel concept that it is the decreased level of APC that is responsible for the decreased DNA repair capacity, which is the cellular mechanisms underlying carcinogenesis in normal breast epithelial cells. Our preliminary data indicate that APC protein interacts with base excision repair proteins, including proliferating cell nuclear antigen (PCNA) and apurinic/apydmidinic endonudease (APE). We hypothesize that the normal levels of APC promote formation of an active complex with PCNA and APE that facilitates repair of abasic DNA through a base excision repair pathway thereby preventing accumulation of gene mutations in normal breast epithelial cells. Decreased levels of APC result in inappropriate binding of the PCNA/APE-complex at the abasic DNA, decreased base excision repair activity, accumulation of gene mutations, and transformation of normal breast epithelial cells. To test this hypothesis, we will use human normal breast epithelial cell lines treated with DNA-damaging mammary carcinogens. We will: (1) Determine that the carcinogen exposure attenuates APC gene expression in normal breast epithelial ceils; (2) Characterize the structure-function relationships of APC with PCNA and APE; (3) Utilize a novel base excision repair assay system with functional purified repair complexes to characterize changes in the dynamics of these complexes in carcinogen-treated normal breast epithelial cell lines; and (4) Examine the function of APC as a PCNA recruiting factor onto abasic DNA to regulate base excision repair activity in carcinogen-treated and untreated normal breast epithelial cells. This project will, for the first time, provide a novel paradigm for understanding the molecular basis for APC function in DNA damage-induced base excision repair and the transformation of normal breast epithelial cells and will facilitate development of chemotherapeutics for prevention of breast cancer progression.

描述（由申请人提供）：我们的总体目标是确定腺瘤性结肠息肉病（APC）基因在DNA损伤诱导的DNA修复活性和乳腺癌发生中的作用。APC的下调是乳腺癌中的主要现象，但其在这种疾病中的作用以及正常乳腺上皮细胞中致癌作用的分子改变均未被表征。在过去，已经研究了突变APC在各种癌症中的作用。在我们的研究中，我们提出了一个非常新颖的概念，即APC水平的降低是导致DNA修复能力降低的原因，这是正常乳腺上皮细胞癌变的细胞机制。我们的初步数据表明，APC蛋白与碱基切除修复蛋白，包括增殖细胞核抗原（PCNA）和脱嘌呤/脱嘧啶核酸内切酶（APE）相互作用。我们假设正常水平的APC促进与PCNA和APE形成活性复合物，通过碱基切除修复途径促进无碱基DNA的修复，从而防止正常乳腺上皮细胞中基因突变的积累。APC水平的降低导致PCNA/APE复合物在无碱基DNA处的不适当结合、碱基切除修复活性的降低、基因突变的积累以及正常乳腺上皮细胞的转化。为了验证这一假设，我们将使用人类正常乳腺上皮细胞系与DNA损伤乳腺癌物质处理。我们将：（1）确定致癌物暴露减弱正常乳腺上皮细胞中APC基因表达;（2）表征APC与PCNA和APE的结构-功能关系;（3）利用具有功能性纯化修复复合物的新型碱基切除修复测定系统来表征这些复合物在致癌物处理的正常乳腺上皮细胞系中的动力学变化;和（4）检查APC作为PCNA募集因子到脱碱基DNA上以调节致癌剂处理和未处理的正常乳腺上皮细胞中的碱基切除修复活性的功能。该项目将首次为理解APC在DNA损伤诱导的碱基切除修复和正常乳腺上皮细胞转化中的分子基础提供一种新的范式，并将促进预防乳腺癌进展的化疗药物的开发。

项目成果

DNA polymerase β as a novel target for chemotherapeutic intervention of colorectal cancer.

• DOI: 10.1371/journal.pone.0016691
• 发表时间: 2011-02-02
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Jaiswal AS;Banerjee S;Aneja R;Sarkar FH;Ostrov DA;Narayan S
• 通讯作者: Narayan S

A novel function of adenomatous polyposis coli (APC) in regulating DNA repair.

腺瘤性息肉大肠杆菌（APC）在调节DNA修复中的新功能。

• DOI: 10.1016/j.canlet.2008.06.024
• 发表时间: 2008-11-28
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Jaiswal, Aruna S.;Narayan, Satya
• 通讯作者: Narayan, Satya

Assembly of the base excision repair complex on abasic DNA and role of adenomatous polyposis coli on its functional activity.

• DOI: 10.1021/bi102000q
• 发表时间: 2011-03-22
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Jaiswal AS;Narayan S
• 通讯作者: Narayan S

Molecular mechanism of adenomatous polyposis coli-induced blockade of base excision repair pathway in colorectal carcinogenesis.

• DOI: 10.1016/j.lfs.2015.08.019
• 发表时间: 2015-10-15
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Narayan S;Sharma R
• 通讯作者: Sharma R

A novel inhibitor of DNA polymerase beta enhances the ability of temozolomide to impair the growth of colon cancer cells.

• DOI: 10.1158/1541-7786.mcr-09-0309
• 发表时间: 2009-12
• 期刊: Molecular cancer research : MCR
• 作者: Jaiswal AS;Banerjee S;Panda H;Bulkin CD;Izumi T;Sarkar FH;Ostrov DA;Narayan S
• 通讯作者: Narayan S