Urokinase (uPA), a member of the serine protease family, and its cell surface receptor (uPAR) have been implicated in promoting the progression of various human malignancies including hormone dependent malignancies such as breast and prostate cancer. However, the underlying molecular mechanisms regulating uPA production in breast and prostate cancer progression are poorly understood. / In the current studies, we have examined the role of uPAR in breast cancer progression by developing a homologous model of uPAR overexpression by a rat breast cancer cell line Mat B III. Overexpression of uPAR resulted in increased breast cancer growth, invasion and metastasis in vitro and in vivo. Development of this syngeneic breast cancer model allowed me to examine the ability of the anti-estrogen, tamoxifen (TAM) and a synthetic active site inhibitor of uPA, 4-iodo benzo[b]thiophene-2-carboxamidine (B-428), to prevent breast cancer progression. TAM and B-428 treatment alone or in combination effectively prevented breast tumor growth, invasion and metastasis in vitro and in vivo. Morever, TAM and B-428 treatments caused a decrease in uPAR gene expression and protein production. 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. Regulation of uPA production by androgens in prostate cancer was then examined in the androgen insensitive PC-3 cells transfected with the functional human androgen receptor cDNA (PC-3T). Androgens down regulate uPA gene expression and protein production in androgen sensitive PC-3T cells. Furthermore, restoration of androgen responsiveness in PC-3T cells caused a dramatic decrease in tumor growth, invasion and metastasis in vitro and in vivo. Due to the ability of sex steroids to inhibit uPA gene expression, I have also examined the correlation between hormone sensitivity and uPA expression in several hormone responsive (HR) and hormone insensitive (HI) breast and prostate cancer cell lines. uPA mRNA was expressed only in the highly invasive, HI breast (MDA-231) and prostate (PC-3) cell lines. Failure of uPA mRNA expression in the minimally invasive, HR breast (MCF-7) and prostate (LnCAP) cells was due to transcriptional suppression of uPA gene. Southern blot analysis usi
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35651 |
| Date | January 1998 |
| Creators | Xing, Rosie Hongmei, 1968- |
| Contributors | Rabbani, S. A. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001635579, proquestno: NQ44631, Theses scanned by UMI/ProQuest. |
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