Retinoid prevents transformation of cultured mammary glands by procarcinogens but not by many activated carcinogens

Abstract

Specific hormones^1,2 in concert with epidermal growth factor³ induce the mouse mammary gland in serum-free whole organ culture to undergo two physiological cycles³, each consisting of lobuloalveolar development, differentiation and involution (regression). In addition, chemical carcinogens cause an epithelial transformation, which is operationally defined by the presence of nodule-like alveolar lesions that have escaped the hormonal controls of lobuloalveolar development^4–9. The transformed mammary glands are also dysplastic, metaplastic^4,5 and oncogenic⁶. Chemically analogous non-carcinogens have little or no transforming activity^4,8. Furthermore, transformation by the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) is prevented, suppressed and apparently reversed by retinoid⁵ (chemical related to vitamin A). The retinoid acts anti-promotionally, that is, it apparently blocks the transformation process at a stage after the interaction of carcinogen with critical cellular target(s). We report here that the ability of retinoid to prevent mammary gland transformation anti-promotionally is largely limited to carcinogens (procarcinogens) that require metabolic activation to become reactive. Mammary gland transformations caused by low concentrations of procarcinogens are blocked by the retinoid 2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione (retinylidene dimedone). In contrast, transformations by five activated carcinogens and by high concentrations of procarcinogens are not prevented. The present findings suggest important limitations of retinoids in the prevention of epithelial transformation by chemical carcinogens.