Different responses associated with PKCbeta1 and PKCepsilon overexpression in normal and tumoral mammary cell lines

ALEJANDRO J. URTREGER; VALERIA C. GROSSONI; ELISA D. BAL DE KIER JOFFÉ

Anaheim, EEUU.

Congreso; 96th Annual Meeting of the American Association for Cancer Research; 2005

American Association for Cancer Research (AACR)

Previously we have demonstrated that the overexpression of different PKC isoforms induced alterations compatible with the acquisition of a malignant phenotype in normal murine mammary cells. In this work we compare the effect of the overexpression of classic PKCb1 and novel PKCe in murine mammary normal (NMuMG) and tumor-derived (LM3) cells. Although the stable overexpression of PKCb1 in LM3 cell line induced an increase in the proliferative capacity both in monolayer, and when cells were cultured at low density (clonogenic capacity 38.07±15.2% vs 19.13±7.5% in LM3-vector, p<0.05), a significant reduction in the tumorigenic capacity (tumor take 35±10% vs 85±21% in LM3-vector, p<0.05) and lung metastatic incidence (14% vs 57% in LM3-vector, p<0.05) was observed. This in vivo behavior could be associated with an inhibition of its anchorage independent growth capacity and a marked reduction in urokinase secretion (2±0.9 vs 37±15 IU/mg/24h in LM3-vector, p<0.05), as well as with the re-expression of extracellular fibronectin (FN) fibrils. Contrarily, in the normal cell context, the overexpression of the same PKCb1 induced a 5 fold reduction in the clonogenic capacity (p<0.05) of NMuMG cells while a significant increase in uPA secretion was observed. However, PKCb1 also induced the upregulation of FN expression and fibrils formation. Regarding PKCe, its expression both in normal and tumoral contexts, did not modulate proteases secretion, but induced an increase in anchorage-independent growth. Moreover mice inoculated with LM3-PKCe cells presented a higher incidence (100% vs 57% in LM3-vector, p<0.05) and size of spontaneous lung metastasis from than those inoculated with LM3-vector. Our results suggest that PKCb1 may behave as a tumor suppressor, while PKCe would be promoting mammary carcinogenesis and malignant progression.