Naslov (srp)

Analiza ekspresije kljuĉnih molekula PTEN/PI3K/mTOR signalnog puta i ABC transportera kod trostruko negativnih karcinoma dojke i njihova povezanost sa histopatološkim i kliniĉkim parametrima : doktorska disertacija

Autor

Prvanović, Mirjana, 1980-

Doprinosi

Brajušković, Goran, 1968-
Ivković-Kapicl, Tatjana, 1971-
Tatić, Svetislav, 1960-
Tanić, Nikola, 1968-
Milovanović, Zorka, 1960-
Savić-Pavićević, Dušanka, 1972-

Opis (srp)

Trostruko negativni karcinomi dojke su klinički i genetički visoko heterogena grupa humanihmaligniteta a zbog varijabilnog odgovora na terapiju predstavljaju jedan od glavnih izazova zasavremeno društvo, istraţivače i kliničare. TNBC ne eksprimiraju molekularne markere, estrogenskireceptor-ER, progesteronski receptor-PR i receptor za humani epidermalni faktor rasta 2-HER2.Navedeni molekularni markeri su ključni za izbor prave terapije i u direktnoj su vezi sa kliničkimponašanjem, rezistencijom na hemioterapeutike i ishodom bolesti.PTEN/PI3K/AkT/mTOR (PAM) signalni put i prekomerna ekspresija ABC transportera mogu bitiodgovorni za rezistenciju na hemoterapeutike. U vezi sa tim, cilj ove studije bio je utvrđivanjebioloških mehanizama koji su u osnovi rezistencije na hemioterapiju.PAM signalni put je značajan za progresiju humanih tumora a abnormalna aktivacija PAMsignalnog puta jedan je od najčešće poremećenih signalnih puteva u karcinomima dojke. Zato jejedan od osnovnih ciljeva ove studije bio ispitivanje imunoekspresionog profila PTEN, PI3K imTOR protein i ABCB1 (MDR1) membranskog transportera i njihova povezanost i sa kliničkim ihistopatološkim parametrima, tokom i ishodom bolesti.U cilju utvrđivanja molekularnih mehanizama odgovornih za redukciju ili potpuni gubitakekspresije PTEN proteina, urađena je analiza gubitka heterozigotnosti (LOH), RT-qPCR metodom,kao pretpostavljenog najčešćeg mehanizma inaktivacije PTEN tumor supresor gena. Ekspresioniprofili PTEN, PI3K, mTORproteina i MDR1 transportera dobijeni su imunohistohemijskom (IHC)analizom.Pokazali smo da je suprimirana ili odsutna PTEN ekspresija sa visokom ekspresijom PI3K i mTORproteina u asocijaciji sa lošim ishodom bolesti. Potvrdili smo da su PTEN delecije glavnimehanizam i uzrok smanjene ili odsutne ekspesije PTEN proteina. Takođe, pokazali smo da seagresivno ponašanje i češće javljanje metastaza TNBC tumora mogu pripisati značajno češćemgubitku heterozigotnosti (LOH) PTEN tumor supresor gena. Homozigotne delecije (ne ihemizigotne) bi mogle biti potencijalni marker metastatske bolesti i dobar indikator (pokazatelj)prognoze TNBC tumora...

Opis (srp)

Biologija - Molekularna biologija tumora / Biology- Tumor molecular biology Datum odbrane: 11.10.2022.

Opis (eng)

Triple negative breast cancers are a clinically and genetically highly heterogenous group of humantumours and, due to their variable response to therapy, represent one of the main challenges formodern society, researchers and clinicians. TNBCs do not express molecular markers, estrogen-ER,progesterone-PR, and human growth epidermal factor 2-HER2. These molecular markers arecrucial for choosing the right therapy and are directly related to clinical behiavior, resistence tochemotherapeutics and disease outcome. The PTEN/PI3K/Akt/mTOR (PAM) signaling pathwayand overexpression of the ABCB1 transporter may be responsible for resistance tochemiotherapeutics. In this regard, the aim of this study was to determine the biologicalmechanisams underlying chemotherapy resistance. The PAM signaling pathway is one of the mostcommonly disrupted signaling pathways in breast cancers. Therefore, one of the main objectives ofthis study was to examine the immunoexpression profile of PTEN, PI3K and mTOR proteins andexpression profile of ABCB1 (MDR1) membrane transporter and their association with clinical andhistopathological parameters, course of disease and disease outcome. In order to determine themolecular mechanisams responsible for the reduction or complete loss of the PTEN gene allele, weperformed LOH analysis as the presumed most common mechanism of PTEN tumour suppressorgene inactivation. Loss of heterozigosity (LOH) of the PTEN tumour suppressor gene waspreformed by RT-qPCR method and the expression profile of PTEN, PI3K, mTOR proteins andMDR1 transporter by IHC analysis. . Suppresed or absent PTEN expression with high expressionof PI3K and mTOR proteins was found to be associated with poor disease outcome. PTEN deletionsare a mayor cause of reduced or absent PTEN protein expression. It has been esthablished thatMDR1 could be responsible for multidrug resistance to TNBC tumour chemotherapy due to a morefrequent and high expression score. It was found that aggressive behavior and more frequentoccurrence of the TNBC tumor metastases can be attributed to significally more frequent loss ofheterozigosity (LOH) of the PTEN tumour suppressor gene. Homozygous (but not hemyzigotic)could be a potential marker of metastasis formation and a good predictor (indicator) of TNBCoutcome. These data could contribute to the development of personalized medicine and theestablishment of new therapeutic approaches. In other words, a logical strategy in the therapeuticapproach, could be simultaneously targeting molecular markers of PTEN/PI3K/mTOR signalingpathway with MDR1 membrane pump in treatment of TNBC patients.

Jezik

srpski

Datum

2022

Licenca

Ovo delo je licencirano pod uslovima licence
Creative Commons CC BY-NC-ND 3.0 AT - Creative Commons Autorstvo - Nekomercijalno - Bez prerada 3.0 Austria License.

http://creativecommons.org/licenses/by-nc-nd/3.0/at/legalcode

Predmet

OSNO - Opšta sistematizacija naučnih oblasti, Molekularna biologija

PTEN; PI3K; mTOR; proteinska ekspresija; delecije gena; trostruko negativan karcinom dojke; MDR1; rezistencija na terapiju

OSNO - Opšta sistematizacija naučnih oblasti, Molekularna biologija

PTEN; PI3K; mTOR; protein expression; gene deletions; triple negative breast cancer; MDR1; multidrug resistance

577.2:616-006(043.3)