DNA SEQUENCE COPY NUMBER ABNORMALITIES IN HUMAN BREAST CANCER

这个项目的总体目标是识别基因，当基因异常时， 有助于疾病的进展和/或耐药性的发展 乳腺癌。现在提出的研究是建立在我们早先的基础上的 人类大量DNA序列拷贝数异常的观察 应用荧光原位杂交(FISH)技术检测乳腺癌 比较基因组杂交。许多经常出现的 我们已经确定的异常与已知的 致癌基因。因此，我们现在试图识别和表征这些基因。 常见异常区域并利用这些信息进行改进 预测和治疗。(1)我们已将一个普遍存在的区域本地化 将拷贝数增加到约2Mb宽的染色体部分 20q13。我们现在将通过高分辨率分析进一步缩小这一区域 在其他肿瘤中，完全发展为跨越P1/YAC重叠群 这个区域，识别和表征映射到这个区域的基因和 找出导致乳腺癌进展的基因(S)。(2)我们 将使用CGH和FISH来识别DNA序列拷贝数异常 与乳房化疗耐药的发生有关 并确定分子细胞遗传学的程度 在人类乳腺癌亚群中观察到的紊乱是由缺陷引起的 在细胞周期检查点基因中。(3)细胞粘附性鉴定 分子E-钙粘附素作为候选抑癌基因 16q22+突变缺失在乳腺癌细胞系中的失活 剩下的等位基因。我们现在将确定E-钙粘素是否 在原发性乳腺肿瘤中以同样的方式灭活，并探索 协同基因阿尔法、贝塔和伽马突变的可能性 连环蛋白和纽蛋白也参与了E-钙粘蛋白介导的丢失 粘附力。

The overall goal of this project is to identify genes that, when aberrant, contribute to progression and/or to development of drug resistance in breast cancer. The studies proposed now are built on our earlier observations of numerous DNA sequence copy number abnormalities in human breast cancer using fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). Many of the frequent abnormalities that we have identified are not associated with known oncogenes. Thus, we now seek to identify and characterize genes in these regions of common abnormality and to use this information to improve prognostication and therapy. (1) We have localized a region of commonly increased copy number to an approximately 2 Mb wide portion of chromosome 20q13. We will now further narrow this region by high resolution analysis of additional tumors, complete development of a P1/YAC contig spanning this region, identify and characterize genes that map to this region and identify the gene(s) that contribute to breast cancer progression. (2) We will use CGH and FISH to identify DNA sequence copy number abnormalities that are associated with the development of chemoresistance in breast cancers and to determine the extent to which molecular cytogenetic disarray observed in a subset of human breast cancers is caused by defects in cell cycle checkpoint genes. (3) We have identified the cell adhesion molecular, E-cadherin, as a candidate tumor suppressor gene that is inactivated in breast cancer cell lines by deletion of 16q22 plus mutation of the remaining allele. We will now determine if E-cadherin is inactivated in the same way in primary breast tumors and explore the possibility that mutations in collaborating genes alpha, beta and gamma- catenin and vinculin also contribute to loss of E-cadherin mediated adhesion.