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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

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

12 Issues per year


IMPACT FACTOR 2015: 2.710
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Online
ISSN
1437-4315
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Volume 393, Issue 12 (Dec 2012)

Issues

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

Stefanie R. Mullins
  • Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
  • Present Address: MedImmune, Cambridge, UK
/ Mansoureh Sameni
  • Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
/ Galia Blum
  • Departments of Microbiology & Immunology and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
  • Present Address: School of Pharmacy, Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel
/ Matthew Bogyo
  • Departments of Microbiology & Immunology and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
/ Bonnie F. Sloane
  • Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
  • Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
/ Kamiar Moin
  • Corresponding author
  • Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
  • Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
  • Email:
Published Online: 2012-11-13 | DOI: https://doi.org/10.1515/hsz-2012-0252

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.

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

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

About the article

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


Received: 2012-07-12

Accepted: 2012-10-04

Published Online: 2012-11-13

Published in Print: 2012-12-01


Citation Information: Biological Chemistry, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2012-0252. Export Citation

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