Nuclear Receptor Interactions in Breast Cancer: The Role of Kinase Signaling Pathways

摘要

Retinoids and rexinoids are vitamin A derivatives, which cause growth inhibition and/or apoptosis in various cell types, including some breast cancer cells. Retinoids bind and activate the nuclear receptor RAR, whereas rexinoids specifically bind to the related receptor RXR. While retinoids like RA inhibit the growth of estrogen receptor (ER) positive and not ER negative breast cancer cells, rexinoids appear to have activity in both ER positive and ER negative models. In addition, it has been reported that the rexinoid bexarotene can prevent the development of multidrug resistance following exposure to chemotherapy agents. In this report I describe studies of the interactions of different nuclear receptors in breast cancer cells. I have studied how expression of ER affects the phosphorylation status and activity of RAR , and found that reexpression of either ER or increases phosphorylation of RAR and also increases the activity of MAPK and PKC pathways. I have also studied how rexinoids modulate the activity of the SXR/RXR heterodimer, and have found that several rexinoids suppress activation of SXR by SXR agonist such as Rifampicin and the chemotherapeutic agent Taxol, which may provide a mechanism to explain how rexinoids can prevent the development of drug resistance.