The role of cadherin,beta-catenin,and AP-1 in retinoid-regulated carcinoma cell differentiation and proliferation

Vitamin A derivatives (retinoids) are potent regulators of cell proliferation and differentiation. Retinoids inhibit the function of the oncogenic AP-1 and beta-catenin/TCF pathways and also stabilize components of the adherens junction, a tumor suppressor complex. When treated with retinoic acid (RA), the breast cancer cell line, SKBR3, undergoes differentiation and reduction in cell proliferation. The present work demonstrates that in SKBR3 cells, which exhibit high AP-1 activity, RA-regulation of cadherin expression and function, but not changes in AP-1 (or beta-catenin/TCF) signaling, is responsible for the epithelial differentiation. However, cadherin function and recruitment of beta-catenin to the membrane is not required for RA to regulate DNA synthesis in these cells. RA also reduces the activity of an AP-1 and TCF-sensitive cyclin D1 reporter in SKBR3 cells in a manner that is independent of the TCF site. In contrast, in SW480 cells, which have high levels of beta-catenin/TCF signaling, the activity and retinoid responsiveness of the cyclin D1 promoter was markedly inhibited by mutation of the TCF site. These data indicate that the remarkably broad effects of RA on the growth and differentiation of many different epithelial cancers may well be explained by the ability of RA to differentially regulate the activity of RAR/RXR, AP-1, and beta-catenin/TCF pathways.