Urokinase (uPA), a serine protease is produced in abundance by a variety of malignancies including breast cancer. A critical requirement in this process is localization of uPA and its ability to cause matrix degradation within the malignant cell milieu, achieved via its cell surface receptor (uPAR), expressed by tumor cells. We have examined the role of urokinase receptor (uPAR) in tumor invasion and metastasis by developing a syngeneic model of uPAR overexpression in a rat breast cancer cell line Mat B-IIT using gene transfer technique Cells overexpressing uPAR showed 5-10 fold higher invasive capacity. Inoculation of these cells into the mammary fad pad of female Fischer rats resulted in the development of tumors of significantly larger volume and tumor metastasis at liver, spleen and lymph nodes. Using this model of uPAR overexpression by the rat breast cancer cell line Mat B-III, we have examined the ability of the non-steroidal anti-estrogen, tamoxifen (TAM) and of a selective synthetic inhibitor of uPA, 4-iodo benzo[b]thiophene-2carboxamidine (B-428) to inhibit expression of uPA and uPAR as well as cell growth, invasion and metastasis of wild type Mat B-IU cells and of cells overexpressing uPAR (Mat B-III-uPAR). Both TAM and B-428 inhibited uPAR gene transcription and decreased the proliferative and invasive capacity of Mat B-III and Mat B-III-uPAR. The effects of TAM and B-428 were more pronounced when these agents were tested in combination. Both control and experimental cells (1x10' cells) were inoculated orthotopically into the mammary fat pad of syngeneic female Fisher rats and animals were infused i.p. with either TAM and B-428 alone or in combination for two weeks. Control animals receiving vehicle alone developed large tumors and macroscopic métastases to lungs, liver and lymph nodes. In contrast to this, experimental animals receiving TAM and B-428 showed a significant decrease in primary tumor volume as well as metastasis. Combination therapy had especially marked effects in blocking progression of the primary tumor in experimental animals inoculated with the highly aggressive Mat B-IH- uPAR cells. These results underscore the utility of anti-proteolytic agents (B-428) in addition to standard hormone therapy (TAM) in advanced breast cancer patients where the uPA/uPAR system plays a key role in tumor progression.
|Original language||English (US)|
|Number of pages||1|
|Journal||Fibrinolysis and Proteolysis|
|Issue number||SUPPL. 3|
|State||Published - Dec 1 1997|
ASJC Scopus subject areas