An osteopontin promoter polymorphism is associated with aggressiveness in breast cancer

Abstract

Abstract. Metastasis-related genes are deregulated in cancer by aberrant expression or splicing. Here, we analyzed polymorphic sites in the osteopontin promoter as potential contributors to aberrant expression in breast cancers. This study comprised 241 breast cancer specimens, for which DNA from normal surrounding tissue was available for 111, and 65 healthy breast samples. The polymorphic site in position -443 of the promoter was associated with tumor grade. As expected, there was no association between promoter single nucleotide polymorphisms (SNPs) and tumor stage or 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 RNA 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 histological 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. Our results corroborate that the osteopontin promoter SNPs -443 (rs11730582) and -1748 (rs2728127) are important for gene expression and breast cancer aggressiveness.

Role of osteopontin in the pathophysiology of cancer

“…A detailed study of 241 breast cancer specimens in comparison with DNA from surrounding normal tissue as well as healthy breast samples revealed that the polymorphic site in position −443 of the promoter was associated with tumor grade. This very site, but not others (at −1748 or −1776), showed differences between ER-positive and ER-negative breast cancers and between PR-positive and PR-negative breast cancers, indicating that the SPP1 promoter SNPs −443 (rs11730582) and −1748 (rs2728127) are important for breast cancer aggressiveness (Ramchandani and Weber, 2013). Melanoma metastases that were homozygous for the −443C allele expressed significantly higher levels of SPP1 mRNA compared with those that were either heterozygous (−443T/C) or homozygous for the −443T allele.…”

Osteopontin at the Crossroads of Inflammation and Tumor Progression

“…iOPN was found in dendritic cells [73–75], macrophages [76], and nerve cells [77]. Indeed, iOPN localizes to the nucleus of 293 cells where it mediates cell duplication through association with polo-like kinase 1 [54], whereas in fibroblasts, iOPN plays a role in cell migration [78]. Moreover, deficient expression of iOPN in natural killer (NK) cells causes impaired expansion and increased apoptosis of these cells following stimulation with IL-15, resulting in defective immune response to viral infection and tumor cells [79].…”

Role of osteopontin in the regulation of human bladder cancer proliferation and migration in T24 cells

“…In addition, a number of studies have demonstrated that OPN promoted tumor invasion and metastasis and regulated MMP-9 secretion (27)(28)(29)(30)(31). OPN was shown to combine with integrin αvβ3 and activate NF-κB (nuclear factor-κB) through the PI3K/Akt/IKK (κB kinase inhibitor) signaling pathway, increasing the secretion of urokinase-type plasmi nogen activator A (uPA) and promoting tumor invasion (32,33).…”