title: Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway.
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 μM 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.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 110, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Chen
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Tu
authors.forename: Ching-Shui
authors.initials: CS
authors.lastname: Huang
authors.forename: Ching-Shyang
authors.initials: CS
authors.lastname: Chen
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: Hsiao-Wei
authors.initials: HW
authors.lastname: Lin
authors.forename: Chia-Hwa
authors.initials: CH
authors.lastname: Lee
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chang
authors.forename: Chien-Hsi
authors.initials: CH
authors.lastname: Chang
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.forename: Wen-Sen
authors.initials: WS
authors.lastname: Lee
authors.forename: Yuan-Soon
authors.initials: YS
authors.lastname: Ho
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D051419:Paxillin / Q000378:metabolism*; D011379:Prognosis; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger; D015398:Signal Transduction / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D051419:Paxillin; D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D008249:Protein-Lysine 6-Oxidase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases