Utjecaj postoperativne antihormonske terapije anastrozolom i tamoksifenom na obrasce N-glikozilacije IGG-a u žena s rakom dojke

doctoral thesis

• Title (english): The impact of postoperative antihormonal therapy with anastrozole and tamoxifen on N-glycosylation patterns of IGG in women with breast cancer
• Author: Borna Rapčan
• Mentor: Gordan Lauc (mentor)
• Committee member: Miranda Sertić (predsjednik povjerenstva)
• Committee member: Toma Keser (član povjerenstva)
• Committee member: Tajana Silovski (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of biochemistry and molecular biology); Zagreb
• Defense date and country: 2025-01-10, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Rak dojke trenutno je najčešće dijagnosticirani tip raka u žena. Trenutne metode nedovoljno dobro prate i
predviđaju reakcije pacijenata na liječenje antihormonskim lijekovima, izlažući pacijente potencijalno
nepoželjnim nuspojavama tih lijekova. N-glikani plazmatskih proteina i imunoglobulina G (IgG) pokazani su kao
biomarkeri mnogobrojnih bolesti, posebno onih s izraženim upalnim ili metaboličkim komponentama poput
dijabetesa, hipertenzije, kardiovaskularnih bolesti i raka. Ovo istraživanje istraživalo je strukturne promjene Nglikana
IgG-a prateći 40 pacijenata s rakom dojke Luminal A i Luminal B podtipova tijekom najviše 9 mjeseci.
Protokol je uključivao novorazvijeni automatizirani protokol koji je uključivao izolaciju IgG, denaturaciju
proteina, fluorescentno obilježavanje glikana, pročišćavanje i konačnu analizu pomoću kapilarne gel elektroforeze
s laserski induciranom fluorescencijom. Rezultati su sugerirali značajnu ulogu modificiranih glikana u progresiji
raka dojke, otkrivajući karakteristične trendove u načinu na koji anastrozol i tamoksifen izazivaju različite reakcije.
Rezultati upućuju na povezanost anastrozola sa smanjenom sijalilacijom i povećanom sržnom fukozilacijom, dok
je tamoksifen korelirao s povećanom sijalilacijom i smanjenom sržnom fukozilacijom. Ova promatranja sugeriraju
potencijalne imunomodulatorne učinke: anastrozol potencijalno slabije smanjuje upalu sistemskim smanjenjem
razina estrogena, dok tamoksifen svojim specifičnijim djelovanjem direktno manje utječe na razine estrogena u
tijelu i proizvodi manji proupalni učinak. Ovo istraživanje snažno naglašava važnost uzimanja u obzir specifičnih
karakteristika glikana kako bi se razumjeli dinamični mehanizmi koji potiču progresiju raka dojke i učinci ciljanih
terapija.

Abstract (english)

Breast cancer is currently the most commonly diagnosed type of cancer in women. Current methods inadequately
track and predict patient reactions to antihormonal treatments, exposing patients to potentially undesirable side
effects of these drugs. N-glycans of plasma proteins and immunoglobulin G (IgG) have been shown as biomarkers
for numerous diseases, especially those with pronounced inflammatory or metabolic components such as diabetes,
hypertension, cardiovascular diseases, and cancer. This study investigated structural changes in IgG N-glycans in
40 patients with Luminal A and Luminal B subtypes of breast cancer over a maximum of 9 months. The protocol
included a newly developed automated procedure involving IgG isolation, protein denaturation, glycan fluorescent
labeling, purification, and final analysis using capillary gel electrophoresis with laser-induced fluorescence. The
results suggested a significant role of modified glycans in breast cancer progression, revealing characteristic trends
in how anastrozole and Tamoxifen induce different reactions. The results indicate the association of anastrozole
with reduced sialylation and increased core fucosylation, while Tamoxifen correlated with increased sialylation
and decreased core fucosylation. These observations suggest potential immunomodulatory effects: Anastrozole
potentially reduces inflammation less by systemically lowering estrogen levels, while Tamoxifen, with its more
specific action, directly affects estrogen levels in the body less and produces a lesser pro-inflammatory effect. This
study strongly emphasizes the importance of considering specific glycan characteristics to understand the dynamic
mechanisms driving breast cancer progression and the effects of targeted therapies.

• Keywords: N-glikozilacija; N-glikani; fibrilacija atrija; N-glikani imunoglobulina G; N-glikani ukupnih plazmatskih proteina; UHPLC
• Keywords (english): N-glycosylation; N-glycans; atrial fibrillation; immunoglobulin G N-glycans; total plasma protein N-glycans; UHPLC
• Language: croatian
• URN:NBN: urn:nbn:hr:163:965000
• Promotion: 2025
• Study programme: Title: Pharmceutical-biochemical sciences - doctoral study - university study; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti u području biomedicine i zdravstva (doktor/doktorica znanosti u području biomedicine i zdravstva)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2025-03-31 12:33:45