A molecular role for lysyl oxidase in breast cancer invasion

Dawn A. Kirschmann, Elisabeth A. Seftor, Sheri F.T. Fong, Daniel R.C. Nieva, Colleen M. Sullivan, Elijah M. Edwards, Pascal Sommer, Katalin Csiszar, Mary J.C. Hendrix

Research output: Contribution to journalArticle

261 Scopus citations

Abstract

We identified previously an up-regulation in lysyl oxidase (LOX) expression, an extracellular matrix remodeling enzyme, in a highly invasive/metastatic human breast cancer cell line, MDA-MB-231, compared with MCF-7, a poorly invasive/nonmetastatic breast cancer cell line. In this study, we demonstrate that the mRNA expression of LOX and other LOX family members [lysyl oxidase-like (LOXL), LOXL2, LOXL3, and LOXL4] was observed only in breast cancer cells with a highly invasive/metastatic phenotype but not in poorly invasive/nonmetastatic breast cancer cells. LOX and LOXL2 showed the strongest association with invasive potential in both highly invasive/metastatic breast cancer cell lines tested (MDA-MB-231 and Hs578T). To determine whether LOX is directly involved in breast cancer invasion, LOX antisense oligonucleotides were transfected into MDA-MB-231 and Hs578T cells, and found to inhibit invasion through a collagen IV/laminin/gelatin matrix in vitro compared with LOX sense oligonucleotide-treated and untreated controls. In addition, treatment of MDA-MB-231 and Hs578T cells with β-aminopropionitrile (an irreversible inhibitor of LOX enzymatic activity) decreased invasive activity. Conversely, MCF-7 cells transfected with the murine LOX gene demonstrated a 2-fold increase in invasiveness that was reversible by the addition of β-aminopropionitrile in a dose-dependent manner. In addition, endogenous LOX mRNA expression was induced when MCF-7 cells were cultured in the presence of fibroblast conditioned medium or conditioned matrix, suggesting a role for stromal fibroblasts in LOX regulation in breast cancer cells. Moreover, the correlation of LOX up-regulation and invasive/metastatic potential was additionally demonstrated in rat prostatic tumor cell lines, and human cutaneous and uveal melanoma cell lines. These results provide substantial new evidence that LOX is involved in cancer cell invasion.

Original languageEnglish
Pages (from-to)4478-4483
Number of pages6
JournalCancer research
Volume62
Issue number15
StatePublished - Aug 1 2002
Externally publishedYes

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    Kirschmann, D. A., Seftor, E. A., Fong, S. F. T., Nieva, D. R. C., Sullivan, C. M., Edwards, E. M., Sommer, P., Csiszar, K., & Hendrix, M. J. C. (2002). A molecular role for lysyl oxidase in breast cancer invasion. Cancer research, 62(15), 4478-4483.