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

Author:

de la Cueva Ana1,Emmerling Michael1,Lim Sarah L1,Yang Shi2,Trackman Philip C3,Sonenshein Gail E4,Kirsch Kathrin H1

Affiliation:

1. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

2. Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA

3. Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, USA

4. Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA

Abstract

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.

Funder

National Institute of Health

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,General Medicine

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