Abstract 4210: An osteopontin promoter polymorphism is associated with aggressiveness in breast cancer.

Abstract

Abstract Background: Like cancer initiation, cancer progression and metastasis are genetically programmed. However, unlike oncogenes metastasis genes are deregulated in cancer by aberrant expression or splicing. We have previously described splicing of the metastasis gene osteopontin in cancers. Here we have analyzed polymorphic sites in the osteopontin promoter as potential contributors to aberrant expression in breast cancers. Methods: This study comprised 241 breast cancer specimens, for 111 of which DNA from normal surrounding tissue was available, and 65 healthy breast samples. One probe set tested the polymorphic promoter sites -66, -443, -1748 and -1776. For comparison, we also investigated non-synonymous DNA sequence variations in the coding region positions 305, 367, 794 and 1025. Results: The polymorphic sites in positions -66 and 305 were not in Hardy-Weinberg equilibrium and hence were not included in further analyses. The polymorphic site in position -443 of the promoter was associated with tumor grade. Expectedly, there was no association of the promoter SNPs with tumor stage or with in situ carcinoma versus cancer, as stage and early transformation are determined by the sampling time more than by tumor genetics. In a subset of samples, osteopontin expression levels had previously been obtained. The allelic distribution in positions -443 and -1748 was distinct between high and low expressors, confirming the importance of promoter SNPs. These two sites also form a haplotype. Osteopontin expression has been associated with breast cancer progression, regardless of the histologic subtype of the cancer. Remarkably, the polymorphic site at -443, but not -1748 or -1776, showed differences between ER positive and ER negative breast cancers and between PR positive and PR negative breast cancers, but there was no association with HER2 status. In five cases, the genotype of the tumor was different from the genotype of the host, implying the possibility of somatic mutations in the osteopontin promoter that may affect expression. The polymorphic sites in positions 367, 794, and 1025 showed one homozygous genotype for all specimens in this study. Conclusion: Our results show that the osteopontin promoter SNPs -443 (rs11730582) and -1748 (rs2728127) are important for gene expression and tumor aggressiveness. Citation Format: Georg F. Weber, Divya Ramchandani. An osteopontin promoter polymorphism is associated with aggressiveness in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4210. doi:10.1158/1538-7445.AM2013-4210