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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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Three-dimensional cultures modeling premalignant progression of human breast epithelial cells: role of cysteine cathepsins

Stefanie R. Mullins1, a / Mansoureh Sameni2 / Galia Blum3, b / Matthew Bogyo3 / Bonnie F. Sloane1, 2 / 1, 2

1Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA

2Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA

3Departments of Microbiology & Immunology and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA

aPresent Address: MedImmune, Cambridge, UK

bPresent Address: School of Pharmacy, Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel

Corresponding author: Kamiar Moin, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; and Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA

Citation Information: Biological Chemistry. Volume 393, Issue 12, Pages 1405–1416, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/hsz-2012-0252, November 2012

Publication History

Received:
2012-07-12
Accepted:
2012-10-04
Published Online:
2012-11-13

This article offers supplementary material which is provided at the end of the article.

Abstract

The expression of the cysteine protease cathepsin B is increased in early stages of human breast cancer. To assess the potential role of cathepsin B in premalignant progression of breast epithelial cells, we employed a 3D reconstituted basement membrane overlay culture model of MCF10A human breast epithelial cells and isogenic variants that replicate the in vivo phenotypes of hyperplasia (MCF10AneoT) and atypical hyperplasia (MCF10AT1). MCF10A cells developed into polarized acinar structures with central lumens. In contrast, MCF10AneoT and MCF10AT1 cells form larger structures in which the lumens are filled with cells. CA074Me, a cell-permeable inhibitor selective for the cysteine cathepsins B and L, reduced proliferation and increased apoptosis of MCF10A, MCF10AneoT and MCF10AT1 cells in 3D culture. We detected active cysteine cathepsins in the isogenic MCF10 variants in 3D culture with GB111, a cell-permeable activity-based probe, and established differential inhibition of cathepsin B in our 3D cultures. We conclude that cathepsin B promotes proliferation and premalignant progression of breast epithelial cells. These findings are consistent with studies by others showing that deletion of cathepsin B in the transgenic MMTV-PyMT mice, a murine model that is predisposed to development of mammary cancer, reduces malignant progression.

Keywords: activity-based probes; breast cancer; cysteine cathepsins; premalignant progression; protease inhibitors

Supplementary Article Materials

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