Nuclear Receptor Interactions in Breast Cancer: The Role of Kinase Signaling Pathways
Annual summary 1 Jul 2003-30 Jun 2004
MCGILL UNIV MONTREAL (QUEBEC)
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Retinoids are vitamin A derivatives, which cause growth inhibition, differentiation andor apoptosis in various cell types, including some breast cancer cells. In general, estrogen receptor ER-positive cells are retinoic acid RA sensitive, whereas ER-negative cells are resistant. In this report, I show that ER-negative MDA-MB-231 cells are strongly growth inhibited by retinoids in combination with a PKC inhibitor. While neither RA nor GF109203X GF has a significant growth inhibitory effect in these cells, RAGF potently suppress proliferation and induce apoptosis. Moreover, GF was found to enhance RA-induced transcriptional activation of an RARE reporter construct. Expression of phosphorylated as well as total PKC alpha and delta was decreased by GF and this was potentiated by RA. In addition, treatment with GF caused a sustained activation of ERK12 and p38-MAPK. Importantly, inhibition of ERK but not p38 or JNK suppressed apoptosis induced by RAGF, indicating that activation of ERK is specifically required. In support of this novel finding, the ability of other PKC inhibitors to cause apoptosis in combination with RA correlates with ability to cause sustained activation of ERK. Moreover, it appears that inhibitiondownregulation of PKC delta is specifically involved.
- Medicine and Medical Research