Differential Regulation of Lacto-/Neolacto- Glycosphingolipid Biosynthesis Pathway Reveals Transcription Factors as Potential Candidates in Triple-Negative Breast Cancer.

Ruichao Zeng,Michelle M Hill,Ahmed Mohamed,Kum Kum Khanna

doi:10.3390/cancers13133330

Ruichao Zeng, Michelle M Hill + Show 2 more

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https://doi.org/10.3390/cancers13133330

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Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer with limited treatment options. Glycosylation has been implicated in cancer development, but TNBC-specific glycosylation pathways have not been examined. Here, we applied bioinformatic analyses on public datasets to discover TNBC-specific glycogenes and pathways, as well as their upstream regulatory mechanisms. Unsupervised clustering of 345 glycogene expressions in breast cancer datasets revealed a relative homogenous expression pattern in basal-like TNBC subtype. Differential expression analyses of the 345 glycogenes between basal-like TNBC (hereafter termed TNBC) and other BC subtypes, or normal controls, revealed 84 differential glycogenes in TNBC. Pathway enrichment showed two common TNBC-enriched pathways across all three datasets, cell cycle and lacto-/neolacto- glycosphingolipid (GSL) biosynthesis, while a total of four glycosylation-related pathways were significantly enriched in TNBC. We applied a selection criterion of the top 50% differential anabolic/catabolic glycogenes in the enriched pathways to define 34 TNBC-specific glycogenes. The lacto-/neolacto- GSL biosynthesis pathway was the most highly enriched, with seven glycogenes all up-regulated in TNBC. This data led us to investigate the hypothesis that a common upstream mechanism in TNBC up-regulates the lacto-/neolacto-GSL biosynthesis pathway. Using public multi-omic datasets, we excluded the involvement of copy-number alteration and DNA methylation, but identified three transcription factors (AR, GATA3 and ZNG622) that each target three candidate genes in the lacto-/neolacto- GSL biosynthesis pathway. Interestingly, a subset of TNBC has been reported to express AR and GATA3, and AR antagonists are being trialed for TNBC. Our findings suggest that AR and GATA3 may contribute to TNBC via GSL regulation, and provide a list of candidate glycogenes for further investigation.

Highlights

Breast cancer (BC) is the most common cancer and leading cause of cancer death worldwide in females [1]
We found that Triple-negative breast cancer (TNBC) exhibits a unique glycogene expression profile compared to normal-like and other BC subtypes
An initial list of glycogenes was compiled from the Glycangene database (GGDB) (http:, a manual review of glycosylation-re//acgg.asia/ggdb2/, accessed on 1 March 2017), a manual review of glycosylation-related lated pathways in KEGG and a comprehensive literature review [31,32,33,34]

Summary

Introduction

Breast cancer (BC) is the most common cancer and leading cause of cancer death worldwide in females [1]. BC treatment choice is based on the hormone receptor expression of the tumour, with hormone- and receptor-targeted therapies achieving longterm outcomes for oestrogen receptor-positive (ER+), progesterone receptor-positive (PR+). Approximately 15% of BC cases lack ER, PR and HER2 expression (termed triple-negative breast cancer, TNBC), often occurring in premenopausal women and displaying aggressive features [3]. With the lack of hormone- or receptor-targeted therapies, TNBC is generally treated by surgery and postoperative chemotherapy with limited efficacy, which results in tumour progression and relapse [2]. TNBC with residual disease after neoadjuvant chemotherapy can rapidly progress within 3 to 5 years, and TNBC with relapse showed less than 1-year median overall survival [5,6,7]. There is an urgent need to understand the oncogenic mechanisms underlying TNBC, and to develop early diagnostic biomarkers and novel therapeutic targets for TNBC

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