Published in Cancer Detection and Prevention 1997; 21(5):452-459.

Protease Levels in Breast, Ovary, and Other Gynecological Tumor Tissues: Prognostic Importance in Breast Cancer

Clarissa Ruppert, MDa, Silke Ehrenforth, MDb, Inge Scharrer, Profb, and Ernst Halberstadt, Profa

aDepartment of Gynecology and Oncology, Obstetrics and Gynecology Center, bDepartment of Angiology, Internal Medicine Center, Johann Wolfgang Goethe Universitat Frankfurt/Main, Frankfurt, Germany

Address all correspondence and reprint requests to: Clarissa Ruppert, MD, Universitatsfrauenklinik Frankfurt, Theodor-Stern-Kai 7,60596 Frankfurt, Germany.

ABSTRACT: Proteolytic destruction of basement membrane and tumor surrounding is a prerequisite of invasion and metastasis. In 587 frozen samples of malignant and nonmalignant tissue of breast, uterus, vulva, and ovary, levels of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-I (PAI-1) were examined with enzyme-linked immunosorbent assay ELISA and cathepsin D (cath D) with radioimmunoassay. UPA, PAI-1 and cath D were raised in malignant tissue with significantly higher levels in breast cancer (uPA, PAI-1) and ovarian cancer (cath D). TPA levels were lower in malignant tissue. In 393 primary breast cancer samples, uPA, PAI-1, and cath D were not related to other prognostic factors, whereas tPA levels were significantly raised in prognostic more favorable carcinomas. Over a follow-up period up to 46 months (median 30 months) the log-rank test showed in the whole group of breast cancer patients a significantly higher rate of relapse (p < 0.05) and death (p < 0.001) with tPA levels <2.5 ng/mg. PAI-1 levels >3 ng/mg were associated with shorter overall (p < 0.02; p = 0.01), disease-free (p < 0.008; p < 0.01), and metastasis-free (p < 0.04; p = 0.005) survival in all patients and in the node-negative subgroup, respectively. Higher uPA and cath D levels were not associated with rate of relapse or death over this follow-up period. The prognostic value of tumor-associated proteases could be of interest also in ovarian and cervical cancer.

KEY WORDS: cathepsin D, gynecological tumors, plasminogen activator inhibitor I, proteases, tissue plasminogen activator, urokinase.