A loss-of-function polymorphism in the propeptide domain of the LOX gene and breast cancer.
نویسندگان
چکیده
The lysyl oxidase (LOX) gene reverted Ras transformation of NIH 3T3 fibroblasts and tumor formation by gastric cancer cells, which frequently carry mutant RAS genes. The secreted lysyl oxidase proenzyme is processed to a propeptide (LOX-PP) and a functional enzyme (LOX). Unexpectedly, the tumor suppressor activity mapped to the LOX-PP domain, which inhibited tumor formation and the invasive phenotype of NF639 breast cancer cells driven by human epidermal growth factor receptor-2/neu, which signals via Ras. A single-nucleotide polymorphism, G473A (rs1800449), resulting in an Arg158Gln substitution in a highly conserved region within LOX-PP, occurs with an average 473A allele carrier frequency of 24.6% in the HapMap database, but was present in many breast cancer cell lines examined. Here, we show that the Arg-to-Gln substitution profoundly impairs the ability of LOX-PP to inhibit the invasive phenotype and tumor formation of NF639 cells in a xenograft model. LOX-PP Gln displayed attenuated ability to oppose the effects of LOX, which promoted a more invasive phenotype. In a case-control study of African American women, a potential association of the Gln-encoding A allele was seen with increased risk of estrogen receptor (ER)-alpha-negative invasive breast cancer in African American women. Consistently, LOX gene expression was higher in ER-negative versus ER-positive primary breast cancers, and LOX-PP Gln was unable to inhibit invasion by ER-negative cell lines. Thus, these findings identify for the first time genetic polymorphism as a mechanism of impaired tumor suppressor function of LOX-PP and suggest that it may play an etiologic role in ER-negative breast cancer.
منابع مشابه
Association between HIC1 and RASSF1A Promoter Hypermethylation with MTHFD1 G1958A Polymorphism and Clinicopathological Features of Breast Cancer in Iranian Patients
Background: Ras-associated domain family 1 (RASSF1A) and hypermethylated in cancer (HIC1) genes are methylated more frequently in breast cancer. Genetic factors that alter the DNA methylation levels in normal and tumor tissues could therefore influence the susceptibility to this tumor phenotype. Objective: We determined the frequency of aberrant methylation of HIC1 and RASSF1A gene promoters an...
متن کاملFokI and BsmI Polymorphisms of the VDR Gene and Breast Cancer Risk
Introduction: Vitamin D fulfills its crucial role in cell proliferation and death through signal transduction into the nucleus by vitamin D receptor (VDR). Recent studies have depicted the association between VDR gene polymorphisms and different cancers, including breast cancer. This study attempted to consider the relationship between VDR gene polymorphisms and breast cancer risk among women i...
متن کاملFokI and BsmI Polymorphisms of the VDR Gene and Breast Cancer Risk
Introduction: Vitamin D fulfills its crucial role in cell proliferation and death through signal transduction into the nucleus by vitamin D receptor (VDR). Recent studies have depicted the association between VDR gene polymorphisms and different cancers, including breast cancer. This study attempted to consider the relationship between VDR gene polymorphisms and breast cancer risk among women i...
متن کاملPTEN Gene Expression and Its Association with rs10490920 SNP in Breast Cancer
Introduction: The PTEN gene, also known as MMAC1 or TEP1, is a tumor suppressor gene. One of the important polymorphisms of this gene is the rs10490920 SNP. The purpose of this study was to determine the PTEN gene expression and its relation to changes in rs10490920 polymorphism in breast cancer. Methods: In this study, 40 breast cancer patients and 10 healthy controls were considered. The expr...
متن کاملAssociation between the Functional Polymorphism of Vascular Endothelial Growth Factor Gene and Breast Cancer: A Meta-Analysis
The vascular endothelial growth factor (VEGF) gene single-nucleotide polymorphism involved in the regulation of the protein levels has been implicated in breast cancer. However, the published studies have produced contentious and controversial results. Herein, we performed a meta-analysis (from January to October 2013); to further evaluate the association between +936 C/T polymorphism and the r...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Cancer research
دوره 69 16 شماره
صفحات -
تاریخ انتشار 2009