Glycosylation and its implications in breast cancer

ABSTRACT

Introduction: For decades, the role of glycans and glycoproteins in the progression of breast cancer and other cancers have been evaluated. Through extensive studies focused on elucidating the biological functions of glycosylation, researchers have been able to implicate alterations in these functions to tumor formation and metastasis.

Areas covered: In this review, we summarize how changes in glycosylation are associated with tumorigenesis, with emphasis on breast cancers. An overview of the changes in N-linked and O-linked glycans associated with breast cancer tumors and biofluids are described. Recent advances in glycomics are emphasized in the context of continuing to decipher the glycosylation changes associated with breast cancer progression.

Expert opinion: While changes in glycosylation have been studied in breast cancer for many years, the clinical relevance of these studies has been limited. This reflects the inherent biological and clinical heterogeneity of breast cancers. Glycomics analysis lags behind the advances in genomics and proteomics, but new approaches are emerging. A summary of known glycosylation changes associated with breast cancer is necessary to implement new findings in the context of clinical outcomes and therapeutic strategies. A better understanding of the dynamics of tumor and immune glycosylation is critical to improving emerging immunotherapeutic treatments.

KEYWORDS:

• Biomarkers
• breast cancer
• glycan
• glycosylation
• mass spectrometry

Article highlights

• Breast cancer is a heterogeneous disease that incorporates several distinct entities with remarkably different biological characteristics and clinical behaviors.

• The majority of all current FDA-approved cancer biomarkers are glycoproteins; however, there has been limited specificity and sensitivity of these biomarkers in breast cancer.

• Glycosylation is the enzymatic process that involves the addition of single carbohydrates to proteins or lipids.

• Alterations in glycan expression are due to changes in glycosyltransferase expression or localization, peptide composition, receptor substrates or sugar nucleotide availability.

• Changes in MUC-1 glycosylation have been associated with metastatic potential in various breast cancer subtypes.

• In ER-cancers, an increase in core 2 O-glycans expressing sialyl Lewis^x has been documented and is thought to aid in metastasis.

• Core fucosylation of EGFR results in increases in phosphorylation and dimerization, producing enhanced signaling that is associated with tumor growth and malignancy.

• Recent studies have outlined the predictive potential of specific glycans in detecting poor clinical outcomes in breast cancer.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institutes of Health grants: CA186799-01, CA207779; and the Smartstate SC Centers of Economic Excellence Endowed Centers of Excellence.