OVARIAN CANCER AND HIPPO PATHWAY: CHARACTERIZATION AND ESTROGEN MODULATION

FRAUNHOFFER NICOLAS A.; MEILERMAN ABUELAFIA ANALIA.; STELLA INES; GALLIANO SILVIA; LOPEZ BERGAMI PABLO; VITULLO ALFREDO D.

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2016

Sociedad Argentina de Investigación Clínica

Despite improvements in therapeutic strategies, prognosisfor patients with ovarian cancer (OC) remains dismal. Hormonaltherapy could be an option. Tamoxifen and selective estrogenreceptor modulator, produce only a response of 10% in OC. Akey player in hormonal therapy resistance may be the Hippopathway (HP) bypassing the classical estrogen cascade. YAP isa downstream effector of HP binding to transcriptional co-factorsTEAD. YAP is phosphorylated and restricted to the cytoplasm byMST1/2- and LATS1/2- kinases. To investigate HP involvementin OC, we first analyzed the expression of YAP, LATS1 andMST1/2 by immunochemistry in 14 OC (3 mucinous, 4 serous,4 endometrioid and 3 clear cell). Samples were obtained fromHospital Eva Peron. We found that ovarian cancer presenteddifferent pattern of YAP expression. Endometrioid and clear cellcarcinomas showed strong nuclear YAP expression in extracellularmatrix cells. On the other hand, serous and mucinous carcinomaspresented nuclear YAP signal mainly in cancer cells. LATS1 andMST1/2 showed low expression in all samples. In order to analyzethe effect of 17β-estradiol (E2) on HP in OC, SKOV-3 cells weretreated with 50 and 100 nM of E2. YAP, p-YAP (S127), LATS1and MST1/2 expression was analyzed by western blot at 0, 1 and4h of treatment for each E2 concentration. In addition, cellularlocalization of YAP and TEAD4 was studied by IF. E2 induceda reduction of p-YAP (S127) at 1h in a dose of 100 nM. LATS1and MST1/2 levels were constant in all treatment conditions. Additionally,YAP nuclear staining was 80% higher in 100 nM at 4 hthan control, while TEAD4 was 40% higher. These results showthat YAP presents a differential pattern of expression dependingon OC type, but not LATS1 and MST1/2 kinases which presentlow levels in all OC types. Furthermore, our results suggest thatE2 acts on HP promoting nuclear translocation of YAP. Therefore,these results suggest that HP plays a role in ovarian tumorigenesisand hormonal therapy resistance.