A polymorphism in the lysyl oxidase propeptide domain accelerates carcinogen-induced cancer

Abstract

The propeptide (LOX-PP) domain of the lysyl oxidase proenzyme was shown to inhibit the transformed phenotype of breast, lung and pancreatic cells in culture and the formation of Her2/neu-driven breast cancer in a xenograft model. A single nucleotide polymorphism (SNP, rs1800449) positioned in a highly conserved region of LOX-PP results in an Arg158Gln substitution (humans). This arginine (Arg)→glutamine (Gln) substitution profoundly impaired the ability of LOX-PP to inhibit the invasive phenotype and xenograft tumor formation. To study the effect of the SNP in vivo, here we established a knock in (KI) mouse line (LOX-PPGln mice) expressing an Arg152Gln substitution corresponding to the human Arg158Gln polymorphism. Breast cancer was induced in wild-type (WT) and LOX-PPGln female mice beginning at 6 weeks of age by treatment with 7,12-dimethylbenz(a)anthracene (DMBA) in combination with progesterone. Time course analysis of tumor development demonstrated earlier tumor onset and shorter overall survival in LOX-PPGln versus WT mice. To further compare the tumor burden in WT and LOX-PPGln mice, inguinal mammary glands from both groups of mice were examined for microscopic lesion formation. LOX-PPGln glands contained more lesions (9.6 versus 6.9 lesions/#4 bilateral). In addition, more DMBA-treated LOX-PPGln mice had increased leukocyte infiltrations in their livers and were moribund compared with DMBA-treated WT mice. Thus, these data indicate that the Arg→Gln substitution in LOX-PP could be an important marker associated with a more aggressive cancer phenotype and that this KI model is ideal for further mechanistic studies regarding the tumor suppressor function of LOX-PP.

Polymorphisms in Lysyl Oxidase Family Genes Are Associated With Intracranial Aneurysm Susceptibility in a Chinese Population

“…Lan Ma et al. found that another SNP of LOX (rs1800449) was associated with the susceptibility to coronary artery diseases in Chinese population ( 37 ) and a recent mouse model also suggested that the missense mutation ( p .G473A) caused by rs1800449 could lead to loss tumor suppressor function of the LOX propeptide and thus accelerate carcinogen-induced tumor formation ( 38 ). However, this SNP was not found to be associated with IA in our study.…”

Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer

“…In terms of the impact of genetic alteration, an Arg158Gln substitution in LOX-PP has been shown to be associated with susceptibility of breast [ 71 ], lung [ 72 ], colorectal [ 73 ], and ovarian cancer [ 74 ]. Cueva et al showed that in knock-in strain LOX-PP Gln mice that harbor an Arg152Gln substitution, corresponding to the human Arg158Gln polymorphism of LOX-PP, manifest increased susceptibility to carcinogen-induced breast cancer and hepatic inflammation compared to their wild type counterparts [ 75 ]. With reference to the epigenetic episode, Shao et al demonstrated that 5-azacytidine (5-aza-CR), acting on hypomethylation of DNA by inhibiting DNA methyltransferase, induces LOXL4 upregulation and triggers LOXL4-depedent cell apoptosis in HCC [ 58 ].…”

Expression profiling and microRNA regulation of the LKB1 pathway in young and aged lung adenocarcinoma patients

“…Furthermore, the findings indicated that the observed positive prognostic effect of LOX was associated, at least in part, to miR-30b regulation, confirming the conclusions by Zhong et al ( 64 ) regarding a central role of this miRNA in NSCLC suppression. However, the impact of LOX remains incompletely clear; it is possible that there exists multiple forms of LOX proteins ( 65 ), and it is not known whether the signalling components downstream of LKB1 , including LOX , may be involved in an LKB1 -independent manner; further studies will be required to reach a conclusive point.…”