Abstract 5297: Role of p38 MAPK signaling pathway in the inhibition of breast tumor progression induced by Glypican-3 (GPC3)

Glypican-3 (GPC3) is expressed in normal mammary tissues, but it disappears in tumors. We have transfected the GPC3 gene into murine mammary adenocarcinoma LM3 cells, demonstrating that this proteoglycan acts as a metastasis suppressor. GPC3 reexpressing clones are less metastatic in vivo, showing reduced migration and increased susceptibility to apoptosis in vitro. In relation to GPC3 signaling pathway, we have reported that LM3-GPC3 cells exhibit an inhibition of Akt and canonical Wnt pathways, while they show an activation of non-canonical Wnt and p38 signaling. The aim of this work was to study if the effects of GPC3 on breast tumor progression could be due to p38 activation. LM3-GPC3 or LM3-vector cells were inoculated s.c. into female BALB/c mice. One day later, the p38 inhibitor SB203580 or the vehicle DMSO, were injected i.p. into LM3-GPC3 cells-bearing mice, every 24 h for 10 days. Daily, we recorded the largest and smallest diameter of tumors. Thirty days post-inoculation, mice were killed. We evaluated primary tumor invasiveness behavior by macroscopic examination and histopathological study. We also analyze the spontaneous lungs metastasis, through the counting of macroscopic nodules. LM3-GPC3 and LM3-vector clones generated s.c. tumors showing similar latency and tumorigenic capacity, irrespective of SB203580 treatment (Latency in days, Md [Rg]: 8 [8-10]. Tumorigenicity: 100%). LM3-GPC3 tumors presented a growth rate higher than LM3-vector, while tumors treated with SB203580 grew faster (mm3/day: 17.6±1.9 -GPC3; 15.8±0.9 -vector, 28.2±1.6 -GPC3+SB203580; p