Sensitivity to DNA damage is a common component of hormone-based strategies for protection of the mammary gland.

An early full-term pregnancy significantly reduces the risk of getting breast cancer in women. In animals, this protection can be mimicked by a short-term exposure to physiologic doses of estrogen plus progesterone. Sensitization of p53 and up-regulation of transforming growth factor beta are believed to be important aspects of the mechanism by which protection is imparted. Little is known, however, about the use of this pathway in response to other chemopreventive agents. In this article, we investigated the ability of retinoids, such as 9-cis retinoic acid, all-trans retinoic acid, and N-4-hydroxyphenylretinamide (4-HPR), to sensitize the ductal epithelial cells of virgin mammary glands to DNA damage responses. Using a whole-organ culture system, we observed enhanced cell death in response to gamma-irradiation in the virgin tissues treated with retinoids for 72 hours. These retinoids were partially dependent on p53 and transforming growth factor beta to exert their radiosensitizing effects. However, 4-HPR seemed to sensitize other cells or activate these pathways in a different manner as costimulation with ovarian hormones and 4-HPR was additive, whereas coculture of ovarian hormones and the natural retinoids did not increase amount of death. Taken together, these data suggest that sensitization of the mammary epithelium to p53-dependent apoptosis is a common pathway, which is engaged by retinoids as well as ovarian hormones.