This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Briozzo, P. Articles by Rochefort, H. Search for Related Content PubMed PubMed Citation Articles by Briozzo, P. Articles by Rochefort, H.

In Vitro Degradation of Extracellular Matrix with M_r 52,000 Cathepsin D Secreted by Breast Cancer Cells¹

Unité d'Endocrinologie Cellulaire et Moléculaire, U 148 INSERM, 60, rue de Navacelles, 34090 Montpellier, France

It has been proposed that proteases secreted by cancer cells facilitate metastasis by degrading extracellular matrix. Estrogen receptor-positive breast cancer cells secrete a M_r 52,000 pro-cath-D under estrogen stimulation, whereas this protease is produced constitutively by estrogen receptor-negative cancer cells. We report on the degradation in vitro of extracellular matrix by purified M_r 52,000 cathepsin D (cath-D) and by conditioned media prepared from different cell lines. The purified M_r 52,000 pro-cath-D was autoactivated at pH 4.5 into a M_r 51,000 cath-D and found to digest the extracellular matrix of endothelial bovine corneal cells labeled with [³H]proline or [³⁵S]methionine. Culture medium conditioned by estrogen-treated MCF₇ cells had a similar effect at pH 4.5 but not at pH 7.4. Matrix degradation was totally inhibited by pepstatin. Other breast cancer cells (BT20, MDA-MB231, T₄₇D cells, etc.) and other cancer cells also secreted a pepstatin-sensitive proteinase able to degrade extracellular matrix. By contrast, the U2 variant of MCF₇ cells, which lacks the M_r 52,000 cath-D gene, and the nontumoral epithelial mammary cells secreted a negligible amount of this proteinase. In all conditioned media, the pepstatin-dependent extracellular matrix degrading activity was highly correlated to the M_r 52,000 cath-D concentration measured by immunoenzymatic assay. We conclude that the M_r 52,000 cath-D is the major acidic protease secreted by mammary cancer cells. We suggest that this protease may degrade basement membrane and consequently facilitate tumor invasion when it is released in an acidic microenvironment.

¹ This research was funded by the "Institut National de la Santé et de la Recherche Médicale," the "Groupement des Entreprises Françaises dans la Lutte contre le Cancer," the "Association pour la Recherche sur le Cancer," and the "Faculté de Médecine" of Montpellier.

² Recipient of an internship grant from the "Centre Hospitalier Régional" of Montpellier.

³ Recipient of the "Ministère de la Recherche et de l'Enseignement Supérieur."

⁴ To whom requests for reprints should be addressed.

Received 11/ 6/87. Revised 3/21/88. Accepted 3/29/88.

This article has been cited by other articles:

				S. Erdmann, A. Ricken, C. Merkwitz, I. Struman, R. Castino, K. Hummitzsch, F. Gaunitz, C. Isidoro, J. Martial, and K. Spanel-Borowski The expression of prolactin and its cathepsin D-mediated cleavage in the bovine corpus luteum vary with the estrous cycle Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1365 - E1377. [Abstract] [Full Text] [PDF]

				H. J. Whiteman, M. E. Weeks, S. E. Dowen, S. Barry, J. F. Timms, N. R. Lemoine, and T. Crnogorac-Jurcevic The Role of S100P in the Invasion of Pancreatic Cancer Cells Is Mediated through Cytoskeletal Changes and Regulation of Cathepsin D Cancer Res., September 15, 2007; 67(18): 8633 - 8642. [Abstract] [Full Text] [PDF]

				M. E. Fukuda, Y. Iwadate, T. Machida, T. Hiwasa, Y. Nimura, Y. Nagai, M. Takiguchi, H. Tanzawa, A. Yamaura, and N. Seki Cathepsin D Is a Potential Serum Marker for Poor Prognosis in Glioma Patients Cancer Res., June 15, 2005; 65(12): 5190 - 5194. [Abstract] [Full Text] [PDF]

				V. Laurent-Matha, S. Maruani-Herrmann, C. Prebois, M. Beaujouin, M. Glondu, A. Noel, M. L. Alvarez-Gonzalez, S. Blacher, P. Coopman, S. Baghdiguian, et al. Catalytically inactive human cathepsin D triggers fibroblast invasive growth J. Cell Biol., January 31, 2005; 168(3): 489 - 499. [Abstract] [Full Text] [PDF]

				J. K. Hakala, R. Oksjoki, P. Laine, H. Du, G. A. Grabowski, P. T. Kovanen, and M. O. Pentikainen Lysosomal Enzymes Are Released From Cultured Human Macrophages, Hydrolyze LDL In Vitro, and Are Present Extracellularly in Human Atherosclerotic Lesions Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1430 - 1436. [Abstract] [Full Text] [PDF]

				J. E. Koblinski, J. Dosescu, M. Sameni, K. Moin, K. Clark, and B. F. Sloane Interaction of Human Breast Fibroblasts with Collagen I Increases Secretion of Procathepsin B J. Biol. Chem., August 23, 2002; 277(35): 32220 - 32227. [Abstract] [Full Text] [PDF]

				H. Salahifar, R. C. Baxter, and J. L. Martin Differential Regulation of Insulin-Like Growth Factor-Binding Protein-3 Protease Activity in MCF-7 Breast Cancer Cells by Estrogen and Transforming Growth Factor-{beta}1 Endocrinology, September 1, 2000; 141(9): 3104 - 3110. [Abstract] [Full Text] [PDF]

				P. Strojan, M. Budihna, L. Smid, B. Svetic, I. Vrhovec, J. Kos, and J. Skrk Prognostic Significance of Cysteine Proteinases Cathepsins B and L and Their Endogenous Inhibitors Stefins A and B in Patients with Squamous Cell Carcinoma of the Head and Neck Clin. Cancer Res., March 1, 2000; 6(3): 1052 - 1062. [Abstract] [Full Text]

				A Dragonetti, M Baldassarre, R Castino, M Demoz, A Luini, R Buccione, and C Isidoro The lysosomal protease cathepsin D is efficiently sorted to and secreted from regulated secretory compartments in the rat basophilic/mast cell line RBL J. Cell Sci., January 9, 2000; 113(18): 3289 - 3298. [Abstract] [PDF]

				A. Scorilas, E. P. Diamandis, M. A. Levesque, A. Papanastasiou-Diamandi, M. J. Khosravi, M. Giai, R. Ponzone, R. Roagna, P. Sismondi, and C. Lopez-Otin Immunoenzymatically Determined Pepsinogen C Concentration in Breast Tumor Cytosols: An Independent Favorable Prognostic Factor in Node-positive Patients Clin. Cancer Res., July 1, 1999; 5(7): 1778 - 1785. [Abstract] [Full Text] [PDF]

				M Garcia, N Platet, E Liaudet, V Laurent, D Derocq, J. Brouillet, and H Rochefort Biological and clinical significance of cathepsin D in breast cancer metastasis Stem Cells, November 1, 1996; 14(6): 642 - 650. [Abstract]

				D. W. Visscher, B. Sloane, W. Sakr, M. Sameni, D. Weaver, D. Bouwman, and J. D. Crissman Clinicopathologic Significance of Cathepsin B and Urokinase-type Plasminogen Activator Immunostaining in Colorectal Adenocarcinoma International Journal of Surgical Pathology, April 1, 1994; 1(4): 227 - 234. [Abstract] [PDF]

				D. I. Hradek, B. Kessel, N. Husseinzadeh, and B. C. Moulton Cathepsin D Activity in Human Ovarian Tissues and Ovarian Carcinoma Reproductive Sciences, April 1, 1994; 1(2): 173 - 177. [Abstract] [PDF]

				P Montcourrier, P. Mangeat, C Valembois, G Salazar, A Sahuquet, C Duperray, and H Rochefort Characterization of very acidic phagosomes in breast cancer cells and their association with invasion J. Cell Sci., January 9, 1994; 107(9): 2381 - 2391. [Abstract] [PDF]

				W. Morikawa, K. Yamamoto, S. Ishikawa, S. Takemoto, M. Ono, J.-i. Fukushi, S. Naito, C. Nozaki, S. Iwanaga, and M. Kuwano Angiostatin Generation by Cathepsin D Secreted by Human Prostate Carcinoma Cells J. Biol. Chem., December 1, 2000; 275(49): 38912 - 38920. [Abstract] [Full Text] [PDF]

				R. Navab, E. Chevet, F. Authier, G. M. Di Guglielmo, J. J. M. Bergeron, and P. Brodt Inhibition of Endosomal Insulin-like Growth Factor-I Processing by Cysteine Proteinase Inhibitors Blocks Receptor-mediated Functions J. Biol. Chem., April 20, 2001; 276(17): 13644 - 13649. [Abstract] [Full Text] [PDF]