Role of retinoid receptors in the prevention and treatment of breast cancer.

Retinoids are vitamin A-related compounds that have been found to prevent cancer in animals and humans. In this review, we discuss the role of retinoids and their receptors in the treatment and prevention of breast cancer. The retinoid receptors are expressed in normal and malignant breast cells, and are critical for normal development. In breast cells, when bound by retinoid hormones, these proteins regulate proliferation, apoptosis, and differentiation. The mechanism by which retinoids inhibit breast cell growth has not been completely elucidated, however, retinoids have been shown to affect multiple signal transduction pathways, including IGF-, TGFbeta-, and AP-1-dependent pathways. Retinoids have also been shown to suppress the growth and prevent the development of breast cancer in animals. These agents suppress tumorigenesis in carcinogen-treated rats and in transgenic mice, and inhibit the growth of transplanted breast tumors. These promising preclinical results have provided the rationale to test retinoids in clinical trials for the treatment and prevention of breast cancer. Several retinoids, including all trans retinoic acid and 9-cis retinoic acid, have been shown to have modest activity in the treatment of breast cancer, and these agents are now in clinical trials in combination with cytotoxic agents and anti-estrogens. Another retinoid, 4-HPR, is currently being tested in a human cancer prevention trial. Preliminary results suggest that 4-HPR may suppress breast cancer development in premenopausal women. Future clinical trials will focus on testing new synthetic retinoids that have reduced toxicity and enhanced therapeutic and preventive efficacy.