Retinoids and their receptors in cancer development and chemoprevention.

Retinoids play an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially epithelial cells, mainly through interaction with two types of nuclear receptors: retinoic acid receptors (RARalpha, beta and gamma) and retinoid X receptors (RXRalpha, beta and gamma). Vitamin A deficiency in experimental animals has been associated with a higher incidence of cancer and with increased susceptibility to chemical carcinogens. This is in agreement with the epidemiological studies indicating that individuals with a lower dietary vitamin A intake are at a higher risk to develop cancer. At the molecular level, aberrant expression and function of nuclear retinoid receptors have been found in various types of cancer including premalignant lesions. Thus, aberrations in retinoid signaling are early events in carcinogenesis. Retinoids at pharmacological doses exhibit a variety of effects associated with cancer prevention. They suppress transformation of cells in vitro, inhibit carcinogenesis in various organs in animal models, reduce premalignant human epithelial lesions and prevent second primary tumors following curative therapy for epithelial malignancies such as head and neck, lung, liver, and breast cancer.