Abstract
BackgroundLysyl oxidase (LOX) is an extracellular enzyme essential for the covalent crosslinking of extracellular matrix proteins and may also have additional functions. LOX expression can be both up- and downregulated in cancer and is associated both with tumour suppression and metastasis progression. The G473A polymorphism (rs1800449) results in the Arg158Gln amino acid substitution in the LOX propeptide, compromises its tumour suppressive activity, and was associated with an increased breast cancer risk in a Chinese Han population. In the first hospital-based case-control study in European women, we aimed at investigating the association of LOX expression and the G473A polymorphism with breast cancer risk and survival in unselected and estrogen receptor (ER) negative patients.Methodology/Principal FindingsThe G473A polymorphism was genotyped in 386 breast cancer patients and 243 female controls. Moreover, LOX mRNA expression was quantified in the tumors of 105 patients by qRT-PCR. We found that the minor A-allele of this polymorphism is associated with a later age at breast cancer onset, a trend towards a decreased disease-free and metastasis-free survival, but not with an increased breast cancer risk. LOX mRNA expression was significantly elevated in tumours of patients older than 55 years, postmenopausal patients, estrogen receptor positive tumours, and p53 negative tumours, but was unaffected by G473A genotype in tumours and breast cancer cell lines. High LOX expression was associated with a poor disease-free and metastasis-free survival in ER negative but not ER positive patients. LOX expression was an independent prognostic parameter in multivariate analysis, whereas G473A genotype was not. A small, distinct subgroup of the ER negative patients was identified which exhibited a considerably elevated LOX expression and a very poor disease-free (p = 0.001) and metastasis-free survival (p = 0.0003).Conclusions/SignificanceThis newly identified ER negative/LOX high subgroup may be a suitable collective for future individualized breast cancer diagnosis and therapy.
Highlights
Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase, which catalyses the oxidative deamination of lysine and hydroxylysine residues to aldehydes, initiating the covalent crosslinking of collagens and elastin in the extracellular matrix (ECM) [1,2]
The G473A single nucleotide polymorphism (SNP) affects the amino acid sequence of LOX, and the Gln variant encoded by the minor A-allele has been shown to compromise the tumour-suppressive activity of the LOX propeptide [4]
Such a loss-of-function substitution could lead to an increased cancer risk, and the A-allele was associated with a significantly elevated breast cancer risk in a Chinese Han population [18]
Summary
Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase, which catalyses the oxidative deamination of lysine and hydroxylysine residues to aldehydes, initiating the covalent crosslinking of collagens and elastin in the extracellular matrix (ECM) [1,2]. LOX is a member of a family of lysyl oxidases which includes four additional paralogues, LOXL1–4 [1]. Aberrant expression of these enzymes is associated with a number of human diseases, especially cancer. Lysyl oxidase (LOX) is an extracellular enzyme essential for the covalent crosslinking of extracellular matrix proteins and may have additional functions. The G473A polymorphism (rs1800449) results in the Arg158Gln amino acid substitution in the LOX propeptide, compromises its tumour suppressive activity, and was associated with an increased breast cancer risk in a Chinese Han population. In the first hospital-based case-control study in European women, we aimed at investigating the association of LOX expression and the G473A polymorphism with breast cancer risk and survival in unselected and estrogen receptor (ER) negative patients
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