Molekularno profilisanje i karakterizacija trostruko negativnih i hormonski zavisnih tumora dojke

Abstract

Karcinom dojke je i klinički i genetički heterogeno oboljenje sa varijabilnim odgovorom na terapiju. Estrogenski – ER, progesteronski – PR i receptor za humani epidermalni factor rasta 2 – HER2, najbitniji su biološki markeri na osnovu čije ekspresije se karcinomi dojke dele na: trostruko negativne (TNBC) koji ih ne eksprimiraju i na hormonski zavisne (ER+) tumore koji eksprimiraju ER, a pokazuju varijabilnu ekspresiju PR i HER2. Ovi markeri ključni su i za izbor terapije. TNBC i ER+ karcinomi dojke se rezlikuju po svom kliničkom ponašanju, karateristikama i agresivnosti. TNBC je daleko agresivniji. Navedene razlike posledica su genetičkih lezija čije bi tumačenje moglo da doprinese razvoju novih strategija u terapiji ovih tumora. U vezi sa tim, osnovni cilj ove studije bio je utvrđivanje amplifikacionog obrasca odabrane grupe onkogena, FGFR1, c-MYC, EGFR i CCND1, u oba tipa karcinoma dojke kao i povezivanje njihovog amplifikacionog statusa sa kliničkim tokom i ishodom bolesti. Rezistencija na sistemsku terapiju je osnovni problem u tretmanu oba tipa karcinoma dojke. Ovaj problem posebno je izražen kod obolelih od TNBC koji se zbog odsustva ekspresije ER, PR i HER2, tretiraju isključivo citostaticima na koje vrlo često razvijaju rezistenciju. Zato je jedan od osnovnih ciljeva ove studije bio i identifikacija bioloških mehanizama koji leže u osnovi rezistencije na hemioterapiju, odnosno ispitivanje ekspresionog profila BCRP i MRP1 membranskih transportera i njihove povezanosti sa tokom i ishodom bolesti. Amplifikacioni status analiziranih onkogena ispitan je RT-qPCR metodom, a ekspresioni profil membranskih transportera imunohistohemijskom analizom – IHC. Uporednom analizom amplifikacionog profila četiri onkogena u dva tipa karcinoma dojke, utvrđeno je da se drugačije ponašanje, karaketristike i agresivnost TNBC tumora mogu pripisati značajno češćoj amplifikaciji c-MYC onkogena u ovoj grupi tumora...

Breast cancer is both clinically and genetically a heterogeneous disease with variable response to therapy. Based on the expression of tree most important biological markers, estrogen receptor – ER, progesterone receptor – PR and human epidermal growth factor receptor 2 – HER2, breast cancer can be divided into: triple negative (TNBC) that do not express these receptors and hormone dependent (ER+) tumors that express ER and have a variable expression of PR and HER2. These markers are key for determining therapy. TNBC and ER+ breast cancers differ in their clinical behavior, characteristics and aggressiveness. TNBC is by far more aggressive type. Clarification of genetic lesions that induce the mentioned differences could contribute to the development of new therapeutic strategies for these tumors. Therefore, the main aim of this study was to determine the amplification pattern of the selected oncogene group, FGFR1, c-MYC, EGFR and CCND1, in both types of breast cancer, as well as to investigate a possible connection of amplification status of these oncogenes with the clinical course and outcome of the disease. Resistance to systemic therapy is a primary problem in treatment of both types of breast cancer. This problem is especially pronounced in patients with TNBC that, due to the absence of ER, PR and HER2 expression, are only treated with cytostatics to which they frequently develop resistance. For this reason, one of the main aims of this study was to identify biological mechanism that are the basis of chemoresistance, namely, to investigate the expression profiles of BCRP and MRP1 membrane transporters and their connections with the clinical course and outcome of the disease. The amplification profile of the analyzed oncogenes was investigated using RT-qPCR, while the expression profile of the membrane transporters was analysed by immunocytochemistry – IHC....