Role of Retinoid Receptors in the Prevention and Treatment of Breast Cancer

Retinoids are vitamin A-related compounds thathave been found to prevent cancer in animals and humans.In this review, we discuss the role of retinoids andtheir receptors in the treatment and prevention of breast cancer. The retinoid receptors areexpressed in normal and malignant breast cells, and arecritical for normal development. In breast cells, whenbound by retinoid hormones, these proteins regulate proliferation, apoptosis, and differentiation.The mechanism by which retinoids inhibit breast cellgrowth has not been completely elucidated, however,retinoids have been shown to affect multiple signal transduction pathways, including IGF-,TGF-, and AP-1-dependent pathways. Retinoids havealso been shown to suppress the growth and prevent thedevelopment of breast cancer in animals. These agents suppress tumorigenesis in carcinogen-treatedrats and in transgenic mice, and inhibit the growth oftransplanted breast tumors. These promising preclinicalresults have provided the rationale to test retinoids in clinical trials for the treatment andprevention of breast cancer. Several retinoids,including all trans retinoic acid and9-cis retinoic acid, have been shown to havemodest activity in the treatment of breast cancer, and theseagents are now in clinical trials in combination withcytotoxic agents and anti-estrogens. Another retinoid,4-HPR, is currently being tested in a human cancer prevention trial. Preliminary results suggestthat 4-HPR may suppress breast cancer development inpremenopausal women. Future clinical trials will focuson testing new synthetic retinoids that have reduced toxicity and enhanced therapeutic andpreventive efficacy.