Retinoic acid receptor β mediates the growth-inhibitory effect of retinoic acid by promoting apoptosis in human breast cancer cells

Retinoids are known to inhibit the growth of hormone-dependent but not that of hormone-independent breast cancer cells. We investigated the involvement of retinoic acid (RA) receptors (RARs) in the differential growth-inhibitory effects of retinoids and the underlying mechanism. Our data demonstrate that induction of RARβ by RA correlates with the growth- inhibitory effect of retinoids. The hormone-independent cells acquired RA sensitivity when the RARβ expression vector was introduced and expressed in the cells. In addition, RA sensitivity of hormone-dependent cells was inhibited by a RARβ-selective antagonist and the expression of RARβ antisense RNA. Introduction of RARα also restored RA sensitivity in hormone- independent cells, but this restoration was accomplished by the induction of endogenous RARβ expression. Furthermore, we show that induction of apoptosis contributes to the growth-inhibitory effect of RARβ. Thus, RARβ can mediate retinoid action in breast cancer cells by promoting apoptosis. Loss of RARβ, therefore, may contribute to the tumorigenicity of human mammary epithelial cells.