MICROSATELLITE INSTABILITY OF D17S513 ON CHROMOSOME-17 IS ASSOCIATED WITH PROGRESSION OF BREAST-CANCER

Genetic abnormalities of chromosome 17 are frequently found in human b reast cancer. Recently, loss of heterozygosity (LOH) and microsatellit e instability (MSI) studies have shown evidence for the presence of at least several unknown tumor suppressor genes (TSG) on chromosome 17, in addition to the well known TP53 and the breast cancer susceptibilit y gene BRCA1. We have previously reported the establishment of a trans formed human breast epithelial cell (HBEC) system induced by benzo(a)p yrene in vitro that is tumorigenic in an exogenous host. This has allo wed us to develop a cell line designated BP1E-Tp cells. Further studie s have shown that various regions of chromosome 17 in these cells expr essed genomic changes in the forms of LOH and/or MSI, indicating that putative TSGs anchoring in these regions might have been the targets f or the carcinogenic induction. In the present work, we report that nor mal chromosome 17, upon introduced into the BP1E-Tp cells, was able to partially reverse the transformed phenotypes in vitro as well as the tumorigenic phenotypes in vivo, providing direct functional evidence t hat chromosome 17 does harbor unknown TSGs. Moreover, we discovered th at the MSI of D17S513 (located distal to TP53 at 17p13.1), pre-existin g in BP1E-Tp? cells and derived tumors, was abrogated in the BP1E-Tp c ell-chromosome 17 microcell hybrids, or BPIE-Tp-17neo cells, and the d erived tumors. The reversion of this MSI was in association with the p henotypic reversion observed in these cells, thus suggesting that MSI of D17S513 might represent an important event in the progression of br east carcinogenesis. We further confirmed this by analyzing two groups of primary human breast cancers, one group consisted of tumors less t han 2 cm in diameter with negative lymph node, and another group of tu mors larger than 5 cm in diameter with positive lymph nodes. We found that MSI of D17S513 occurred significantly more frequently in the seco nd group of breast cancers (80%) than in the first group (18%). These results led us to conclude that chromosome 17 harbors putative TSGs, w hose inactivation partially accounted for the expression of neoplastic phenotypes of the BP1E-Tp cells, and that MSI of D17S513 represents a genomic change occurring at the late stage of the neoplastic transfor mation of HBECs as well as during the progression of breast cancers.