Nuclear Receptor Interactions in Breast Cancer: The Role of Kinase Signaling Pathways
Abstract
Retinoids are vitamin A derivatives, which cause growth inhibition, differentiation and/or 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, RA+GF 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 ERK1/2 and p38-MAPK. Importantly, inhibition of ERK but not p38 or JNK suppressed apoptosis induced by RA+GF, 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 inhibition/downregulation of PKC delta is specifically involved.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA429094
Entities
People
- Filippa Petterson
Organizations
- McGill University