title: Microsatellite instability of D17S513 on chromosome 17 is associated with progression of breast cancer.
abstract: Genetic abnormalities of chromosome 17 are frequently found in human breast cancer. Recently, loss of heterozygosity (LOH) and microsatellite 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 susceptibility gene BRCA1. We have previously reported the establishment of a transformed human breast epithelial cell (HBEC) system induced by benzo(a)pyrene in vitro that is tumorigenic in an exogenous host. This has allowed us to develop a cell line designated BP1E-Tp cells. Further studies have shown that various regions of chromosome 17 in these cells expressed genomic changes in the forms of LOH and/or MSI, indicating that putative TSGs anchoring in these regions might have been the targets for the carcinogenic induction. In the present work, we report that normal 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 that chromosome 17 does harbor unknown TSGs. Moreover, we discovered that the MSI of D17S513 (located distal to TP53 at 17p13.1), pre-existing in BP1E-Tp? cells and derived tumors, was abrogated in the BP1E-Tp cell-chromosome 17 microcell hybrids, or BPIE-Tp-17neo cells, and the derived tumors. The reversion of this MSI was in association with the phenotypic reversion observed in these cells, thus suggesting that MSI of D17S513 might represent an important event in the progression of breast carcinogenesis. We further confirmed this by analyzing two groups of primary human breast cancers, one group consisted of tumors less than 2 cm in diameter with negative lymph node, and another group of tumors larger than 5 cm in diameter with positive lymph nodes. We found that MSI of D17S513 occurred significantly more frequently in the second group of breast cancers (80%) than in the first group (18%). These results led us to conclude that chromosome 17 harbors putative TSGs, whose 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 transformation of HBECs as well as during the progression of breast cancers.
authors.affiliation: FOX CHASE CANC CTR, BREAST CANC RES LAB, PHILADELPHIA, PA 19111 USA.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: I
authors.initials: I
authors.lastname: Russo
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Russo