Functional variable number of tandem repeats variation in the promoter of proto‐oncogene PTTG1IP is associated with risk of estrogen receptor‐positive breast cancer

Abstract

Genetic polymorphisms in the signalling pathway of estrogen receptor (ER) could modify the risk of breast cancer. A variable number of tandem repeats (VNTR) polymorphism in the promoter of PTTG1IP, pituitary tumor transforming gene binding factor targeted by estrogen receptor a (ERa) in endocrine neoplasia, has been shown to be functional, but its relevance to cancer etiology was unknown. We investigated its association with breast cancer risk by genotyping in 658 patients and 866 controls and further analysed its differential interaction with ERa. We found nine types of alleles ranging from 2 to 9 and 11 repeats that form 29 distinct genotypes and 11 different biallelic repeat numbers. Subjects who carry the six-repeats allele (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.17-1.79), long alleles ( ! 6 repeats) (OR, 1.55; 95% CI, 1.17-2.05) or a high dose of biallelic repeats (OR, 1.38; 95% CI, 1.07-1.77) were at significantly increased risk of cancer. In stratification analysis, these associations consistently manifested in ER-positive breast cancer: in ER positive, PR-positive subtype, genotypes with the six-repeats allele (OR, 1.42; 95% CI, 1.06-1.90), long alleles (OR, 1.77; 95% CI, 1.17-2.67) or a high dose of biallelic repeats (OR, 1.67; 95% CI, 1.19-2.33) were associated with cancer risk; in ER positive, HER2-negative subtype, they were susceptible factors with the ORs being 1.46 (95% CI, 1.06-2.02), 2.06 (95% CI, 1.28-3.32) and 1.85 (95% CI, 1.26-2.71), respectively. Furthermore, functional analysis revealed that an increase in the number of tandem repeats enhances the binding affinity of ERa. The present study provides the first epidemiological evidence that functional regulatory variants of PTTG1IP were associated with the risk of ER-positive breast cancer, further supporting its relevance as one proto-oncogene in breast cancer.

PTTG1-interacting protein (PTTG1IP/PBF) predicts breast cancer survival

“…Also, exposing breast cancer cell cultures to oestrogen has been shown to up-regulate PTTG1IP expression [ 7 ]. It has also been reported that the variable number of tandem repeats in PTTG1IP promoter might be associated with an increased risk of ER-positive breast cancer [ 15 ]. Very few previous reports have correlated the findings with the immunohistochemical expression of PTTG1IP.…”

Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin

“…Expression of PBF has been circumstantially associated with metastasis in patients with breast (17) and thyroid cancer (16), and we recently reported that patients with colorectal cancer who demonstrate extramural vascular invasion have significantly higher PBF expression (18). However, these associations have not been appraised for causality, and the in vitro mechanisms by which PBF induces tumor cell invasion are unclear.…”

“…First, high PBF expression was correlated with distant metastasis at diagnosis, tumor node metastasis (TNM) stage and disease-specific survival in a large series of papillary thyroid cancers (16). Secondly, high PBF promoter activity was associated with poorer clinical outcome and increased metastatic risk in breast cancer (17). Thirdly, colorectal tumors with higher PBF protein expression demonstrated greater vascular invasion (18).…”

Effects of short‐term exposure to inhalable particulate matter on DNA methylation of tandem repeats

“…Although the significance of epigenetic changes in tandem repeats on lung cancer development has been repeatedly demonstrated, the initial determinants of hypomethylation are not yet well understood [Xiang et al, ]. Little research has investigated the interplay among tandem repeats methylation, inflammatory responses, and cellular oxidative stress induced by ambient PM insult.…”