Loss of anti-proliferative effect of all-trans retinoic acid in advanced stage of breast carcinogenesis

Background: Mechanisms by which the inhibitory effect of retinoic acid on tumor growth is attenuated as tumors progress to more advanced stages are unclear. Materials and Methods: This study utilizes a novel cell culture system of human breast epithelial cells (HBEC). Immortal (M13SV1), weakly tumorigenic (M13SV1-R2), and highly tumorigenic (M13SV1-R2N1) transformed Type I HBEC were derived sequentially from the same parental Type I HBEC (stem cells) developed from reduction mammoplasty of healthy women. Effects of all-trans retinoic acid (AT-RA) on the growth, protein expression of RAR-α, β and γ, and RARE transcriptional activation were determined. Results and Conclusion: AT-RA reduces proliferation rates of immortal and weakly tumorigenic cells, but not highly tumorigenic cells. This loss of response of highly tumorigenic cells to AT-RA is associated with overexpression of p185^c-erbB2/neu. It is not associated with decreased RAR-α, β or γ expression, or activation by AT-RA; RAR-α, β and γ are expressed and AT-RA increases RARE transcriptional activity in all cell lines tested in this study.