Role of PKC in Retinoic Acid Regulation of Human Mammary Cancer Cell Proliferation

摘要

Retinoids have anti-tumor effects and a number of clinical trials of retinoids in human breast cancer have been initiated. Although retinoids inhibit proliferation of numerous breast cancer cell lines, responsiveness appears to be limited to estrogen-dependent cells, in which retinoic acid (RA) inhibits estrogen stimulation of proliferation. The proliferative effect of estrogen on mammary cells has been linked to the production of mitogenic growth factors and increased expression of surface receptor tyrosine kinases. Growth factor binding to receptor tyrosine kinases activates multiple, interactive signaling pathways, most of which involve sequential activation of serine/threonine protein kinases. Retinoic acid (RA) inhibits signaling between receptor tyrosine kinases and the nucleus. The components of these signaling pathways that serve as targets for RA have yet to be identified. At least two signaling pathways stimulated by receptor tyrosine kinase utilize protein kinase C (PkC) family members as mediators. Because of the relationships between hormone-dependent mammary cell proliferation, RA growth regulation and protein kinase C, we have hypothesized that retinoic acid inhibits the uncontrolled proliferation of mammary carcinoma cells, by increasing the overall activity of PKC%, and/or decreasing the overall activity of PKC%. Two HBC cell lines are used in our study, the hormone- dependent/RA-sensitive T47D cell line and the hormone-independent/RA-resistant MDA-MB-231 line.