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Increased Secretion, Altered Processing, and Glycosylation of Pro-Cathepsin D in Human Mammary Cancer Cells¹

Institut National de la Santé et de la Recherche Medicale, Unité Hormones et Cancer (U 148) (UAC 59 CNRS), 60 Rue de Navacelles, 34090 Montpellier, France

In human mammary cancer cells, pro-cathepsin D (pro-Cath-D) is induced by estrogens and 50% of it is secreted. To determine whether its secretion is characteristic of mammary cells or transformed cells, we compared its production, processing, and glycosylation in primary cultures of normal mammary epithelial cells to those found in breast cancer cell lines. The cytosolic concentration of total cathepsin D (precursor and mature enzyme) measured by enzyme-linked immunosorbent assay was 8 times higher in cancer cells. Its mRNA level estimated by Northern blot analysis was 8 to 50 times higher and its secretion was 30 times higher in cancer cells. Using pulse-chase labeling, the cellular processing of pro-Cath-D was altered in hormone-dependent and -independent breast cancer cells in comparison to normal cells. This alteration resulted in a lower accumulation of mature enzyme, while the secretion and cytoplasmic accumulation of pro-Cath-D were greater in breast cancer cells than in normal cells. NH₄Cl increased secretion of the proenzyme in normal cells but not in cancer cells. The secreted proenzyme was markedly heterogeneous and had a more acidic pI in MCF7 cells than in normal mammary cells. These acidic forms disappeared following endo-ß-N-acetylglucosaminidase H treatment indicating that the structural difference between pro-Cath-D of normal and of cancer mammary cells was located on high mannose or hybrid N-linked oligosaccharides. This difference may be responsible for the altered routing of the pro-Cath-D in breast cancer cells.

¹ This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Faculty of Medicine of Montpellier, the Association pour la Recherche sur le Cancer, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer, and the Ligue Nationale contre le Cancer.

² Recipient of the Ministère de la Recherche et de l'Enseignement Supérieur Fellowship Grant.

³ To whom requests for reprints should be addressed.

Received 2/ 1/89. Revised 4/ 7/89. Accepted 4/17/89.

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