Cloning of Novel Oncogenes Involved in Human Breast Cancer

摘要

While the aberrant overexpression of HER family receptors is known to be involved in breast cancer, the complex nature of the genetic events that trigger the development of breast cancer remain to be identified. The authors have developed, refined, and applied a retrovirus-based gene transfer assay to identify activated oncogenes in breast cancer. Progress during the past year has involved the following: (1) the use of breast carcinoma cell lines for generation of retrovirus expression libraries; (2) development of better functional screens for activated oncogenes, and (3) evaluation of protocols to improve the rescue of cDNAs from the transformed cell populations. The authors have generated several retrovirus-based cDNA expression libraries that represent genes expressed in noninvasive (MCF-7 and T47D) and invasive (MDA-MB4682 and BT549) human breast cancer cell lines. These libraries were introduced into Rat- 1 rodent fibroblasts and RIE-1 rat intestinal epithelial cells, after which transforming activity was assayed. Two isolates from the analyses encode the Rat-1 serine/threonine kinase and the fibroblast growth factor receptor 2 (FGFR2). In the final year of support, the authors characterized the transforming activity of FGFR2 and evaluated possible signaling mechanisms by which it causes transformation. The results show that pharmacologic inhibitors of MEK1/2 potently block FGFR2 transforming activity. (4 figures, 7 refs.).