Present studies in the mammary epithelial cell transformation model in organ culture showed that presence of beta-carotene during the 24 hr treatment (initiation stage) of the glands with the carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA), N-nitrosodiethylamine (DENA) and N-methylnitrosourea (MNU), caused a highly significant (P less than 0.001-0.01) reduction of SCE induced by the same carcinogens. In contrast, 4-hydroxyphenyl retinamide (4-HPR) which is known to act at the promotional stage of carcinogenesis did not show any significant reduction of SCE. Thus findings suggest that beta-carotene can modify the DNA damaging effect of the carcinogens and thereby may also prevent the initiation of the carcinogenic process.

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Second thoracic mammary glands of immature BALB/c female mice were stimulated to pregnancy-like lobuloalveolar (LA) development after 6 days of incubation in a corticosteroid-free step I culture medium containing insulin, prolactin, estradiol, progesterone, and growth hormone. A low basal level (0.0009%) of casein mRNA (mRN4.,) sequences was detectable in the LA glands by a specific cDNA probe. Subsequent incubation of the LA glands for 3 days in medium containing insulin and prolactin or insulin and cortisol failed to elicit mRNAesn above the basal level, indicating that neither prolactin nor cortisol alone can support casein gene expression.However, an increase in mRNA. levels was observed when the 3-day incubation with insulin and cortisol or insulin and prolactin was followed by 3 days of culture in presence of insulin, prolactin, and cortisol. When a 3-day incubation with insulin and prolactin was followed by 3 days in insulin and cortisol medium, mRNAes. levels in the gland remained similar to the basal level. However, a 20-fold increase in the mRNAesn levels ensued when the LA glands were sequentially incubated for 3 days in insulin and cortisol and then for another 3 days in insulin and prolactin medium. After a preincubation in insulin and cortisol medium, the LA glands retained residual cortisol during subsequent incubation in insulin and prolactin medium, and the mRNAes. levels in these glands were related to the level of residual cortisol present. When mRNAesn and the residual cortisol level reached a minimum, addition of fresh cortisol to the medium caused a 20-fold increase in the mRNAesn levels. This indicates that cortisol is a limiting factor in insulin and prolactin medium and its presence is absolutely required for casein gene expression.The requirement that prolactin and cortisol be present for lactogenesis was delineated over 2 decades ago (1, 2). Since then, numerous studies have shown that, during lactation, a marked increase of mammary cell RNA and protein, including casein, is dependent upon stimulation by prolactin and cortisol (3, 4). We have shown that cortisol is required for the maintenance of casein-synthesizing polysomes, poly(A)+RNA synthesis, and casein mRNA (mRNAsn) accumulation in the lactating mammary gland of the mouse (5-7). Moreover, a regulatory action of the glucocorticoid on transcription of the casein gene in the mammary gland in vivo has been demonstrated (7). However, complexities in the animal limit elucidation of the discrete role of polypeptide and steroid hormones which regulate specific expression of the casein gene in breast cells.Fragments of mammary tissue from pregnant mice were demonstrated to be capable of synthesizing casein in a culture medium containing the lactogenic hormones plus insulin (8). This provided an in vitro model for studying molecular responses of the mammary cells to prolactin and glucocorticoid action in a chemically defined medium containing insulin, which is needed for viability of the mammary parenchyma in vitro (9). Subsequen...