Specific isotypes of the retinoic acid receptor (RARs) differentially modulate parameters associated with metastatic spread in triple negative mammary cancer cells

NATALIA AMIGO; LUCIANA CAÑONERO; LIZETH ARIZA BAREÑO; ANDRES BECHIS; DAMIAN DELBART; ALEJANDRO J. URTREGER; LAURA B. TODARO

Congreso; LXV Reunión Científica de la Sociedad Argentina de Investigación Clínica (SAIC); 2020

Sociedad Argentina de Investigación Clínica (SAIC)

Migration and adhesion are highly related to metastatic dissemination and retinoid system is implicated in their modulation. Objective: Evaluate the effect of activating each retinoic acid receptor (RAR) isotype in migration, soluble MMPs activity, adhesion and metastatic potential in LM38-LP and 4T1 triple negative murine cell lines. Both cell lines express all RAR isotypes with the exception of RARb in 4T1 cells. Cells were treated with the RARa agonist AM580 (200 nM), RARb agonist AC55649 (2 uM), RARg agonist BMS961 (50 nM) or vehicle (DMSO). Migratory potential was evaluated by wound healing assays. AM580 and AC55649 reduced LM38-LP migratory capacity while AM580 increased migration in 4T1 cells. MMPs were analyzed by zymography. AM580, AC55649 and BMS961 decreased soluble MMP2 activity in LM38LP. On the contrary, AM580 increased both MMP2 and MMP9 activities in 4T1. Besides, AM580 and AC55649 diminished LM38LP adhesive capacity while AC 55649 increased this potential in 4T1. Finally, a lung colonization assay was performed. Cells were pretreated with the agonists and then inoculated into syngeneic BALB/c mice. While AC55649 increased metastatic potential of LM38-LP cells, BMSS961 increased this potential in 4T1 cells. We hypothesize that the differences in RARb expression between the cell lines could be responsible of opposite biological effects observed. The increase in metastatic potential after RARb/g activation could be associated with the selection of a minority population with high plasticity to colonize the target organ.