Relevance of PTEN loss in brain metastasis formation in breast cancer patients

Abstract

IntroductionWith the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Therefore, our aim was to identify molecular markers associated with the development of brain metastases in breast cancer.MethodsPatterns of chromosomal aberrations in primary breast tumors and brain metastases were compared with array-comparative genetic hybridization (CGH). The most significant region was further characterized in more detail by microsatellite and gene-expression analysis, and finally, the possible target gene was screened for mutations.ResultsThe array CGH results showed that brain metastases, in general, display similar chromosomal aberrations as do primary tumors, but with a notably higher frequency. Statistically significant differences were found at nine different chromosomal loci, with a gain and amplification of EGFR (7p11.2) and a loss of 10q22.3-qter being among the most significant aberrations in brain metastases (P < 0.01; false discovery rate (fdr) < 0.04). Allelic imbalance (AI) patterns at 10q were further verified in 77 unmatched primary tumors and 21 brain metastases. AI at PTEN loci was found significantly more often in brain metastases (52%) and primary tumors with a brain relapse (59%) compared with primary tumors from patients without relapse (18%; P = 0.003) or relapse other than brain tumors (12%; P = 0.006). Loss of PTEN was especially frequent in HER2-negative brain metastases (64%). Furthermore, PTEN mRNA expression was significantly downregulated in brain metastases compared with primary tumors, and PTEN mutations were frequently found in brain metastases.ConclusionsThese results demonstrate that brain metastases often show very complex genomic-aberration patterns, suggesting a potential role of PTEN and EGFR in brain metastasis formation.

Prognostic Role of PTEN Gene Expression and Length of Survival of Breast Cancer Patients in the North East of Iran

“…Thus, developed breast cancer tumours at higher stages expressed PTEN gene less. Previous studies showed that the risk of metastasis of cancerous cells to other tissues is greater in breast cancer patients without PTEN gene expression (Tsutsui et al, 2005;Wikman et al, 2012). This study is consistent with the aforementioned studies.…”

“…After the investigation, cells with less than 10% colouring were considered negative, and those with more than 10% of brown stain were considered positive. Samples were divided into positive and negative degrees considering PTEN gene expression or its lack (Sakr et al, 2010;Wikman et al, 2012).…”

MicroRNA-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis

“…In addition to its role in cell cycle regulation, apoptosis, and angiogenesis, evidence from recent animal and clinical studies indicates that PTEN also contributes to suppression of tumor metastasis (47,48). Reduction of PTEN is likely to facilitate metastasis by enhancing proliferation and inhibiting apoptosis at the metastatic site (49).…”

EGFR and HER2 signaling in breast cancer brain metastasis

“…Additionally, array-comparative genetic hybridization (CGH) that compares patterns of chromosomal aberrations between primary breast cancers and brain metastatic tumors shows that EGFR is overexpressed in 80% of brain metastases compared to only 13% of primary breast tumors (88). Microsatellite analysis for allelic imbalance shows that 64% of brain metastases and 19% primary breast tumors had an allelic imbalance at the PTEN locus in HER2 negative breast cancers (88).…”

“…Microsatellite analysis for allelic imbalance shows that 64% of brain metastases and 19% primary breast tumors had an allelic imbalance at the PTEN locus in HER2 negative breast cancers (88). Primary breast cancers with metastasis to the brain have significant modifications on chromosome 7 and 10 q, specifically on the loci of EGFR and PTEN.…”