Epigenetic hypomethylation and upregulation of GD3s in triple negative breast cancer

Abstract

Background: Breast cancer remains a major health problem in the world. Triple-negative breast cancer (TNBC) is an aggressive subtype with very poor prognosis. Up to now, the mechanism behind TNBC's activity is still unclear and no candidate drug target has been identified. Thus, it is of critical importance to elucidate the pathways in TNBC and identify the relevant biomarkers. Recent studies showed that ganglioside D3 synthase (GD3s) played a very important role in development of cancers. However, the physiological functions and associated pathways of GD3s in TNBC are still unclear.Methods: In silico analysis of the expression of GD3s in TNBC was conducted using The Cancer Genome Atlas (TCGA) and Oncomine databases. The proliferation of breast cancer cells was measured by MTT assay, colony formation by the soft agar method, and migration and invasion using Boyden chamber inserts.The methylation level of the gene encoding GD3s, ST8SIA1, in specimens was assessed by qMS-PCR and in silico using the UCSC gene browser. Protein expression was examined via immunohistochemistry (IHC), qRT-PCR and Western immunoblotting.Results: In silico analysis showed a higher GD3s expression in ER − than ER + breast cancers and GD3s was also highly expressed in TNBC compared to other types of breast cancers. The elevated GD3s expression in TNBC cells and tissues was associated with hypomethylation of the ST8SIA1 gene. Overexpression of GD3s in human breast cancer cells increased their proliferation, migration, invasion and colony formation ability. GD3s expression in breast cancers was closely associated with relapse-free survival (RFS) and overall survival (OS).Conclusions: In summary, these results suggest that GD3s may be a potential biomarker and drug target in treatment of TNBC.

Gastrointestinal adenocarcinoma analysis identifies promoter methylation-based cancer subtypes and signatures

“…In this study, six hypo-methylated clusters for GAC were generated with different OS profiles, the patients’ OS and tumor progression become worse as the methylation level decreases, and MSI was inversely proportional to hypomethylation. Hypomethylation can promote the up-regulation of proto-oncogenes or tumor progression-related genes through various pathways, thereby changing the biological behavior of cancer 26 – 28 , which is consistent with our results. Currently, people are generally keen to study the phenomenon of hypermethylation in cancer.…”

The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology

“…In metastatic melanoma high ST8Sia1 expression is associated with detrimental outcome and higher expression in metastatic lesions, particularly in the brain (201). Recent studies analyzing data from The Cancer Genome Atlas (TCGA) showed an association of high ST8Sia1 expression levels in breast cancer with poor patient survival (202)(203)(204), which is eventually linked to epigenetic hypomethylation of the ST8SIA1 gene (204). As opposed, in another study higher expression of ST8Sia1 mRNA in estrogen receptor (ER) positive breast cancer patients has been associated with higher disease free survival, while no significant difference was found in ER negative patients (205).…”

A comprehensive pan-cancer study of fibroblast growth factor receptor aberrations in Chinese cancer patients

“…FGFR aberrations were harbored by 6.2% (552/8,922) of the patients with lung cancer in our study, with the majority of aberrations occurring in FGFR1 (59.6%, 311/552), followed by FGFR3 (119/552) and FGFR2 (60/552). FGFR4 aberrations were detected in 16 Mutation refers to all non-amplification, non-fusion mutations including insertions or deletions, single base substitutions, multiplenucleotide substitutions, and copy number deletion. N, screened population; amp, amplification.…”

“…For instance, FGFR1 has been reported to be amplified in as many as 19% of squamous cell lung carcinomas (13), 6% of small cell lung carcinomas, and 1% of lung adenocarcinomas (14). FGFR1 amplification is also prevalent in breast cancer, with 15% of hormone receptor-positive breast cancers and 5% triple-negative breast cancers (TNBC) have been found to harbor FGFR1 amplification (15)(16)(17). FGFR2 amplification, which occurs less frequently than FGFR1 amplification, is present in 4-9% of gastric cancers, especially in diffuse-type gastric cancer (18), and is often associated with poor prognosis (19).…”