INVESTIGADORES
URTREGER Alejandro Jorge
congresos y reuniones científicas
Título:
The retinoic acid receptor isotypes alpha and beta regulate migration, adhesion and metalloprotease activity in murine models of breast cáncer
Autor/es:
CAROLINA FLUMIAN; DAMIAN E. BERARDI; STÉFANO M. CIRIGLIANO; MARIA I. DIAZ BESSONE; ELISA D. BAL DE KIER JOFFÉ; ALEJANDRO J. URTREGER; LAURA B. TODARO
Lugar:
San Carlos de Bariloche
Reunión:
Congreso; Third Sudamerican Symposium in Signal Transduction and Molecular Medicine (SISTAM); 2015
Resumen:
Parameters associated with metastatic dissemination as migration, adhesion and metalloprotease (MMPs) secretion are known to be regulated by all trans-retinoic acid (ATRA). ATRA activity is mainly mediated by retinoic acid receptors (RARs), ligand-inducible transcription factors that are members of the superfamily of nuclear hormone receptors. Our goal was to evaluate the effect of specifically activate each RAR isotype in two murine hormone-independent breast cancer cell lines: LM38-LP y 4T1. Both cell lines express all RARs isotypes with the exception of RARb in 4T1 cell line. For the experiments cells were treated for 96h with AM580 (RARa agonist, 200 nM), AC55649 (RARb agonist, 2 uM), BMS961 (RARg agonist, 50 nM) or vehicle (DMSO). The migratory potential was evaluated by a wound healing assay. LM38-LP cell line reduced its migratory capacity in response to AM580 and AC55649. An inverse effect was observed in 4T1 cells which increased the migratory potential after AM580 treatment. Next, conditioned media was prepared in order to evaluate soluble MMPs activity by zymography. AM580, AC55649 and BMS961 pre-treatments decreased soluble MMP2 activity in LM38-LP cells. Conversely, AM580 pre-treatment increased MMP2 and MMP9 in 4T1 cells. Regarding the adhesive potential, we observed that AM580 and AC55649 diminished LM38-LP adhesive capacity while AC 55649 increased this parameter in 4T1 cells. Finally, we performed an experimental lung metastasis assay using LM38-LP cells pre-treated for 144hs. Only AC55649 treatment induced an increase in the number of lung colonies. In conclusion, we hypothesized that the differences in RARb expression between both cell lines might be responsible for the opposite responses to RARa and RARb activation. Surprisingly, the activation of RARb increased the metastatic potential of LM38-LP cells in spite of negative regulation of parameters associated with the metastatic process.