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Pregled bibliografske jedinice broj: 740064

Zbornik radova

Autori: Levanat, Sonja; Trnski, Diana; Uzarevic, Zvonimir; Ozretic, Petar; Musani, Vesna; Sabol, Maja
Naslov: Interactions of Hedgehog-Gli and estrogen receptor signaling pathways in breast cancer cells
( Interactions of Hedgehog-Gli and estrogen receptor signaling pathways in breast cancer cells )
Izvornik: European Journal of cancer / Elsevier (ur.). - Amsterdam : EACR , 2014. S118-S118.
Skup: 23rd Biennial Congress of the European Association for Cancer Research
Mjesto i datum: Munich, Njemačka, 05.-08.07.2014
Ključne riječi: Interactions ; Hedgehog-Gli ; estrogen receptor signaling pathways ; breast cancer cells
( Interactions ; Hedgehog-Gli and estrogen receptor signaling pathways ; breast cancer cells )
Sažetak:
Introduction Hedgehog-Gli (Hh-Gli) signaling pathway is one of the new molecular targets found upregulated in breast tumors. Estrogen receptor alpha (ERα) signaling has a key role in the development of hormone-dependent breast cancer. The aim of this study is to determine the possible combined effects of Hh-Gli pathway inhibitor cyclopamine with ER inhibitor tamoxifen in breast cancer therapy, and to establish a potential interactions between Hh-Gli and ER signaling in breast cancer. Materials and Methods ER-positive MCF-7 and ER-negative SkBr-3 breast cancer cell lines were used. Drug treatments and Competition experiments were with: cyclopamine 0.5-7.5 μM (Toronto Research Chemicals) and tamoxifen 1-10 μM (Toronto Research Chemicals). MTT and cell migration assays were used. Gene expression studies with : cyclopamine (2.5 μM), Shh protein (3 ng/ml), tamoxifen (1 μM for MCF-7 or 5 µM for SkBr-3), β-estradiol (5 nM, Sigma) or cyclopamine + tamoxifen and Transfection with GLI1 and PTCH1 silencing (Life Technologies) in MCF cells were performed, and QRT-PCR with primers for ERα, c-MYC, RPLP0, PTCH1, SMO, GLI1, SHH, andSUFU.Immunofluorescent staining, Immunoprecipitation and Western blot were performed with primary antibodies: anti-Hh (Santa Cruz, sc-9024), anti-ERα (Santa Cruz, sc-8002), anti-Ptch1 (Santa Cruz, sc-6147), anti-Gli1 (Santa Cruz, sc-20687) and Actin (Santa Cruz, sc-1616). Confocal images were examined using the Manders coefficient plugin of the ImageJ software (v 1.45e). Dynabeads Protein G (Life Technologies) were coated with anti-ERα antibody and cell lysates were immunoprecipitated as per manufacturer’s instructions. Results and Discussion ER-positive cells show decreased viability after treatment with cyclopamine, a Hh-Gli pathway inhibitor, as well as after tamoxifen (an ERα inhibitor) treatment. Simultaneous treatment with cyclopamine and tamoxifen on the other hand, causes short-term survival of cells, and only longer treatment decreases cell proliferation. The survival effect is strongest 48 hours after simultaneous treatment with both inhibitors, and we found upregulated Hh-Gli signaling under these conditions. In addition to promoting survival, the combination of these two drugs promotes cell migration and longer treatment decreases Hh-Gli signaling as well as ERα levels. We also show a direct interaction between Shh and ERα. Shh protein is able to bind and activate ERα independently of the canonical Hh-Gli signaling pathway. Conclusion The mechanism which is responsible for the increased viability of ER-positive cell line after combined treatment with cyclopamine and tamoxifen is not clear. Although Hh-Gli signaling seems to be a good potential target for breast cancer therapy, combined treatment of cyclopamine and tamoxifen may induce an opposite effect, providing cells with short-term survival.
Vrsta sudjelovanja: Poster
Vrsta prezentacije u zborniku: Sažetak
Vrsta recenzije: Međunarodna recenzija
Projekt / tema: 098-0982464-2461
Izvorni jezik: eng
Kategorija: Znanstveni
Znanstvena područja:
Temeljne medicinske znanosti
Upisao u CROSBI: Sonja Levanat (Sonja.Levanat@irb.hr), 11. Pro. 2014. u 12:15 sati



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