Breast Cancer in Three Dimensions: Revealing Telomere Dysfunction in Breast Cancer

摘要

The structural re-modeling of the mammalian nucleus is a key feature of cancer cells. Such reorganization of the nucleus impacts the genomic integrity of the cell. Our focus is on the genetic alterations that affect the telomeres (the ends of chromosomes) in breast cancer. In this study, we wished to determine if mutations in either of the two main breast cancer susceptibility genes, known as BRCA1 and BRCA2 can influence the way in which telomeres are organized. To do this, we studied the three-dimensional (30) organization of telomeres in breast cancers derived from BRCA1 and BRCA2 gene mutation carriers. We used breast cancers arising in non-BRCA1/2 mutation carriers as controls. In addition, we studied three cancer cell lines derived from BRCA1-, BRCA2- and non-carriers to see if we found the same effect. There were two main measures-the length of the telomeres and the aggregation of the telomeres (i.e. to what extent telomeres were found 'stuck together')- this is usually the result of chromosomes with broken ends becoming fused. To summarize, the results were not conclusive. It was clear that the BRCA1 and BRCA2 cell lines had shorter telomeres and more aggregations compared with the controls, but in the tumors, the results were less clear. There was, however, a non- significant trend in the same direction as observed in the cell lines. This work is now continuing, and we aim to submit this work for publication in the coming year. The role of MYC in this process is of particular interest, as many BRCA1 tumors show amplification of MYC, and MYC is known to interact with other proteins in the maintenance of telomere length. We are currently analyzing the same set of tumors for MYC amplification by FISH.