Alterations in the glycosylation pattern of alpha-1-glycoprotein may be diagnostic for the detection of breast cancer and/or reducing the effect of chemotherapy in vivo

Kate Doak, Jodi Flaws, Yvonne Cruickshank, Kevin D. Smith

Research output: Chapter in Book/Report/Conference proceedingChapter


Alpha-1-acid glycoprotein AGP is an important binder of drugs in the plasma. Although the binding site is protein in nature, the glycosylation pattern present could still affect the overall conformation of the glycoprotein and could also have implications on access to the binding site. Drugs bound by plasma proteins have reduced efficacy as pharmacological effects are exerted by free unbound drug. The present study aimed to determine if AGP could bind to tamoxifen, the gold standard of treatment for breast cancer, and if, through this binding, AGP could represent a mechanism of resistance to tamoxifen. The glycosylation of AGP was also examined to determine if any disease-specific changes were present in breast cancer and if these disease-specific glycoforms displayed altered binding properties for tamoxifen. The study used different cohorts of patients - healthy individuals, those with untreated breast cancer, those at risk of breast cancer and those with breast cancer being treated with tamoxifen therapy. AGP was isolated by a technique specifically chosen because it did not degrade the glycoprotein structure, thus reflecting the situation in vivo. Drug binding was examined by the use of an intrinsic fluorescence assay. Patients with untreated and tamoxifen treated breast cancer had significantly increased AGP levels compared to healthy individuals. The monosaccharide fucose, which is normally not present on AGP glycosylation in healthy plasma, was found in untreated breast cancer patients. Fucose was also found in some tamoxifen treated samples, which correlated with tamoxifen treatment, with those patients at the end of treatment displaying no fucose indicating no inflammation or disease, thus backing up the standard 5 year treatment period with tamoxifen. Patients with untreated breast cancer displayed a disease specific shift to bisiaylated glycan chains compared with healthy AGP. Tamoxifen treated breast cancer patients showed changes in the oligosaccharide structures over the time course of tamoxifen therapy, reverting to normal at a later time point - also indicated by the monosaccharide analysis. Untreated breast cancer patients were able to bind tamoxifen to a similar extent as healthy AGP. In contrast those at risk and those with tamoxifen treated breast cancer had significantly reduced binding. Although binding was minimal at therapeutic concentrations, the decrease in binding by breast cancer patients could lead to issues regarding toxicity as there would be more free drug in the plasma and therefore this concentration could exceed the therapeutic level.

Original languageEnglish (US)
Title of host publicationOligosaccharides
Subtitle of host publicationFood Sources, Biological Roles and Health Implications
PublisherNova Science Publishers, Inc.
Number of pages29
ISBN (Electronic)9781629483290
ISBN (Print)9781629483283
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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