Serum Pyrrolidone Carboxypeptidase Activity in N-methyl Nitrosourea Induced Rat Breast Cancer

Abstract

Pyrrolidone carboxypeptidase (Pcp) (E.C. 3.4.19.3) is an omega peptidase widely distributed in animal fluids and tissues and hydrolyses N-terminal pyroglutamic residues from biologically active peptides such as gonadotropin releasing hormone (GnRH). Previous results obtained by us showed a decrease in human breast cancer Pcp activity, suggesting that this enzyme activity or its putative substrates may play a mayor role in breast cancer pathogenesis. The aim of the present work is to analyse serum Pcp activity in N-methyl-nitrosourea (NMU) induced rat mammary tumours using pyroglutamyl-β-naphthylamide as substrate. Serum Pcp activity was significantly lower in NMU-treated rats than in controls. Moreover, multiple regression analysis showed a significant correlation between Pcp activity and the number and size of tumours and the body weight of the animals. Since NMU-induced carcinomas are mainly oestrogen-dependent, the decrease observed in Pcp activity may reflect an increase in circulating levels of GnRH that lead to an increase in gonadal steroid hormones production responsible, at least in part, for the initiation and promotion of the disease.

Pyroglutamyl aminopeptidase - NMU - Mammary gland - GnRH - Tumour growth parameters

References

• 1 Flötotto T, Djahansouzi S, Gläser M, Hanstein B, Niederacher D, Brumm C, Beckman M W. Hormones and hormone antagonist: mechanisms of action in carcinogénesis of endometrial and breast cancer.  Horm Metab Res. 2001;  33 451-457
• 2 Imagawa W, Pedchenko V K, Helber J, Zhang H. Hormone/growth factor interactions mediating epithelial/stromal communication in mammary gland development and carcinogenesis.  J Steroid Biochem Mol Biol. 2002;  80 213-230
• 3 Zajchowski D, Sajer R, Webster L. Estrogen inhibits the growth of estrogen receptor-negative, but not estrogen receptor-positive, human mammary epithelial cells expressing a recombinant estrogen receptor.  Cancer Res. 1993;  53 5004-5011
• 4 Jordan V C. Laboratory studies to develop general principles for the adjuvant treatment of breast cancer with antiestrogen: Problem and potential for future clinical applications.  Breast Cancer Res Treat. 1983;  3 73-86
• 5 Russo J, Russo I H. Atlas and histologic classification of tumors of the rat mammary gland.  J Mammary Gland Biol Neoplasia. 2000;  5 187-200
• 6 Gullino P M, Pettigrew H M, Grantham F H. N-nitrosomethylurea as mammary gland carcinogen in rats.  J Natl Cancer Inst. 1975;  54 401-414
• 7 Thompson H J, Adlakha H. Dose-responsive induction of mammary gland carcinomas by the intraperitoneal injection of 1-methyl-1-nitrosourea.  Cancer Res. 1991;  51 3412-3415
• 8 McCormick D L, Adamowski C B, Filks A, Moon R C. Lifetime dose-response relationship of mammary tumor induction by a single administration of N-methyl-N-nitrosourea.  Cancer Res. 1981;  41 1690-1694
• 9 Welsch C W. Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: A review and tribute to Charles Breton Huggins.  Cancer Res. 1985;  45 3415-3443
• 10 Russo J, Gusterson B A, Rogers A E, Russo I H, Wellings S R, van Zwieten M J. Biology of disease; Comparative study of human and rat mammary tumorigenesis.  Lab Invest. 1990;  62 244-278
• 11 Beynon R, Bond J. Proteolytic Enzymes. New York; Oxford University Press 2001
• 12 Cummins P M, O'Connor B. Pyroglutamyl peptidase; an overview of the three known enzymatic forms.  Biochim Biophys Acta. 1998;  429 1-17
• 13 Martínez J M, Prieto I, Ramírez M J, Cueva C, Alba F, Ramírez M. Aminopeptidase activities in breast cancer tissue.  Clin Chem. 1999;  45 1797-1802
• 14 Rivera E S, Andrade N, Martin G, Melito G, Cricco G, Mohamad N, Davio C, Caro R, Bergoc R M. Induction of mammary tumors in rat by intraperitoneal inyection of NMU; histopathology and estral cycle influence.  Cancer Lett. 1994;  86 223-228
• 15 Martínez J M, Ramírez M J, Prieto I, Petzelt C, Hermoso F, Alba F, Arias Saavedra J M, Ramírez M. Human serum pyroglutamyl-ß-naphthylamide hidrolyzing activity during development and aging.  Arch Gerontol Geriat. 1999;  28 31-36
• 16 Kottler M L, Starzec A, Carre M C, Lagarde J P, Martin A, Counis R. The genes for gonadotropin-releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer.  Int J Cancer. 1997;  71 595-599
• 17 Moriya T, Suzuki T, Pilichowska M, Ariga N, Kimura N, Ouchi N, Nagura H, Sasanu H. Inmunochemical expression of gonadotropin releasing hormone receptor in human breast carcinoma.  Pathol Int. 2001;  51 333-337
• 18 Paradiso A, Pezzetta A, Cellamare G, Shittulli F, Marzullo F, Reshkin S J. GnRH receptors in human breast cancer and its contiguous not-involved breast tissue.  J Endocrinol Invest. 2000;  23 90-96
• 19 Huirne J A, Lambalk C B. Gonadotropin-releasing-hormone-receptor antagonists.  Lancet. 2001;  358 1793-1803
• 20 Russo J, Russo I H. Influence of differentiation and cell kinetics in the susceptibility of rat mammary gland to carcinogenesis.  Cancer Res. 1980;  40 2677-2687