Patogenetski mehanizmi hormonske rezistencije stanica raka dojke

master's thesis

• Title (english): Pathogenic mechanisms of hormone resistance in breast cancer cells
• Author: Lucija Kovačević
• Mentor: Natalija Dedić Plavetić (mentor)
• Committee member: Damir Vrbanec (predsjednik povjerenstva)
• Committee member: Nikola Đaković (član povjerenstva)
• Committee member: Natalija Dedić Plavetić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Pathophysiology); Zagreb
• Defense date and country: 2016-07-15, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Pathophysiology

Abstract

Rak dojke je najčešće dijagnosticiran maligni tumor u ženskoj populaciji širom svijeta te se predviđa da će se u otprilike jednoj od osam žena u Hrvatskoj za vrijeme njenog životnog vijeka razviti invazivni karcinom dojke. Receptor za estrogene (ER) izražen je u otprilike 70% novodijagnosticiranih karcinoma dojke i ima važnu ulogu u tumorskom rastu i progresiji. Hormonska terapija predstavlja okosnicu liječenja hormonski ovisnih karcinoma dojke. Usprkos njenoj učinkovitosti, u velikog broja bolesnica, pojavljuje se rezistencija na hormonsko liječenje što predstavlja veliki izazov u odabiru optimalnog načina liječenja. Razumijevanje mehanizama koji doprinose razvoju rezistencije omogućit će razvoj novih i učinkovitijih lijekova. Identificirani su mogući mehanizmi koji dovode do rezistencije na hormonsku terapiju, a često uključuju pojačanu signalizaciju čimbenicima rasta te promjene izražaja i djelovanja estrogenskog receptora. Također, nekoliko studija je istaklo ulogu nekodirajuće RNA (ncRNA) u razvoju rezistencije na hormonsko liječenje. Usprkos ohrabrujućim rezultatima pretkliničkih istraživanja, rezultati kliničkih studija koje su promatrale kombinaciju hormonske terapije s trastuzumabom ili inhibitorima tirozin kinaze (TKI) vrlo su diskutabilni. Kliničke studije koje su se fokusirale na novije lijekove poput mTOR (od engl. mammalian target of rapamycin) inhibitora everolimusa polučile su obećavajuće rezultate. Rezultati randomizirane studije BOLERO-2 koja je evaluirala kombinaciju hormonske terapije i everolimusa u liječenju metastatskih karcinoma dojke s pozitivnim hormonskim receptorima pokazali su značajno produljenje preživljenja do progresije bolesti (PFS, od engl. progression free survival) kod pacijentica liječenih kombinacijom oba lijeka u odnosu na one liječene samo hormonskom terapijom. Cilj ovog rada je dati pregled potencijalnih mehanizama uključenih u razvoj rezistencije na hormonsku terapiju stanica karcinoma dojke.

Abstract (english)

Breast cancer is the most commonly diagnosed cancer in female population worldwide and it is estimated that approximately one out of every eight Croatian women will develop invasive breast cancer over the course of her lifetime. Estrogen receptor (ER) is expressed in approximately 70% of newly diagnosed breast tumors and has an important role in tumor growth and progression. Endocrine therapy forms the backbone of treatment for hormone-dependent breast cancer. Despite the benefits of endocrine therapy, resistance eventually occurs in a large number of patients and represents important clinical challenge in the management of breast cancer. Understanding the mechanism by which these cancers develop resistance would enable the development of new and effective therapeutics. There are many potential mechanisms of resistance to endocrine therapies which have been identified and they often involve enhanced growth factor signaling and changes in the expression or action of the estrogen receptor. Moreover, a few studies have highlighted the role of noncoding RNA (ncRNA) in the development of endocrine resistance.
Clinical trials investigating the combination of endocrine therapy with trastuzumab or the tyrosine kinase inhibitors (TKIs) have given varied results, despite encouraging preclinical data. More promising results come from clinical studies which have focused on novel agents such as the mammalian target of rapamycin (mTOR) inhibitor everolimus. The results from the randomized trial BOLERO-2 evaluating everolimus±endocrine therapy in a selected subgroup of HR-positive metastatic breast cancer patients have demonstrated a significant improvement in progression free survival (PFS) for the combination compared to the endocrine therapy alone. This review serves as an overview of the potential mechanisms involved in the resistance of breast cancer cells to endocrine therapy.

• Keywords: hormonska rezistencija; estrogenski receptor; rak dojke
• Keywords (english): hormonal resistance; estrogen receptor; breast cancer
• Language: croatian
• URN:NBN: urn:nbn:hr:105:304821
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-07-05 11:35:20