Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway

Li Ching Chen, Shih Hsin Tu, Ching Shui Huang, Ching Shyang Chen, Chi Tang Ho, Hsiao Wei Lin, Chia Hwa Lee, Hui Wen Chang, Chien Hsi Chang, Chih Hsiung Wu, Wen Sen Lee, Yuan Soon Ho

Research output: Contribution to journalArticle

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Abstract

The extracellular matrix (ECM) plays a critical role in the development and invasion of primary breast tumors. Lysyl oxidase (LOX), which is an ECM remodeling enzyme, appears to play roles in promoting cancer cell motility and invasion. To ascertain whether LOX overexpression in breast tumor tissues from Asian patients is associated with decreases in metastasis-free and overall survival in breast cancer patients, the mRNA levels of LOX were examined in paired tumor/normal tissue samples using real-time RT-PCR analysis (n = 246 pair-matched samples). To test whether specifically targeting LOX by inhibiting its activity (using beta-aminopropionitrile (β-APN), a LOX inhibitor), mRNA expression (using siRNA), or protein expression (using 25 lM magnolol) attenuates the invasion of MDA-MB-231 breast cancer cells, a cancer cell migration assay was performed. Interestingly, only 78.5% (n = 193) of the breast cancer tumors displayed detectable LOX expression. Nearly 60% (n = 120) of the cases fell into Group 1 (tumor >normal, T > N); in this group, the mean LOX expression in the tumor cells was 20.2-fold greater than in normal cells. However, in Group 2 (normal>tumor, N>T), the LOX expression level in most of the normal tissues examined (80%, 59/73) was less than fivefold greater than in the tumor tissues. The increased level of active LOX in the invasive breast cancer cell line MDA-MB-231 was accompanied by the increased phosphorylation of focal adhesion kinase at Tyr-576 and of paxillin at Tyr-118. We also found that the addition of β-APN (300 μM) and magnolol (25 μM), synergistically inhibited the migration and invasion of MDA-MB-231 cells. In this article, we describe, for the first time, higher expression of a LOX protein in breast tumors compared with normal tissues from Asian patients. Moreover, the results indicate that the inhibition of LOX using magnolol may represent a more desirable strategy for breast cancer therapy than the use of β-APN.

Original languageEnglish
Pages (from-to)989-1004
Number of pages16
JournalBreast Cancer Research and Treatment
Volume134
Issue number3
DOIs
Publication statusPublished - Aug 2012

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Protein-Lysine 6-Oxidase
Paxillin
Focal Adhesion Protein-Tyrosine Kinases
Down-Regulation
Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Extracellular Matrix
Aminopropionitrile
Cell Migration Assays
Messenger RNA
Small Interfering RNA
Cell Movement
Real-Time Polymerase Chain Reaction
Proteins

Keywords

  • Breast cancer
  • FAK
  • Lysyl oxidase
  • Magnolol
  • Metastasis
  • Paxillin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway. / Chen, Li Ching; Tu, Shih Hsin; Huang, Ching Shui; Chen, Ching Shyang; Ho, Chi Tang; Lin, Hsiao Wei; Lee, Chia Hwa; Chang, Hui Wen; Chang, Chien Hsi; Wu, Chih Hsiung; Lee, Wen Sen; Ho, Yuan Soon.

In: Breast Cancer Research and Treatment, Vol. 134, No. 3, 08.2012, p. 989-1004.

Research output: Contribution to journalArticle

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abstract = "The extracellular matrix (ECM) plays a critical role in the development and invasion of primary breast tumors. Lysyl oxidase (LOX), which is an ECM remodeling enzyme, appears to play roles in promoting cancer cell motility and invasion. To ascertain whether LOX overexpression in breast tumor tissues from Asian patients is associated with decreases in metastasis-free and overall survival in breast cancer patients, the mRNA levels of LOX were examined in paired tumor/normal tissue samples using real-time RT-PCR analysis (n = 246 pair-matched samples). To test whether specifically targeting LOX by inhibiting its activity (using beta-aminopropionitrile (β-APN), a LOX inhibitor), mRNA expression (using siRNA), or protein expression (using 25 lM magnolol) attenuates the invasion of MDA-MB-231 breast cancer cells, a cancer cell migration assay was performed. Interestingly, only 78.5{\%} (n = 193) of the breast cancer tumors displayed detectable LOX expression. Nearly 60{\%} (n = 120) of the cases fell into Group 1 (tumor >normal, T > N); in this group, the mean LOX expression in the tumor cells was 20.2-fold greater than in normal cells. However, in Group 2 (normal>tumor, N>T), the LOX expression level in most of the normal tissues examined (80{\%}, 59/73) was less than fivefold greater than in the tumor tissues. The increased level of active LOX in the invasive breast cancer cell line MDA-MB-231 was accompanied by the increased phosphorylation of focal adhesion kinase at Tyr-576 and of paxillin at Tyr-118. We also found that the addition of β-APN (300 μM) and magnolol (25 μM), synergistically inhibited the migration and invasion of MDA-MB-231 cells. In this article, we describe, for the first time, higher expression of a LOX protein in breast tumors compared with normal tissues from Asian patients. Moreover, the results indicate that the inhibition of LOX using magnolol may represent a more desirable strategy for breast cancer therapy than the use of β-APN.",
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AU - Ho, Chi Tang

AU - Lin, Hsiao Wei

AU - Lee, Chia Hwa

AU - Chang, Hui Wen

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AU - Wu, Chih Hsiung

AU - Lee, Wen Sen

AU - Ho, Yuan Soon

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