Hormonally induced elevations of alpha- and beta-casein mRNA levels are blocked by cyclic adenine nucleotide and prostaglandins

Normal mammary gland development during pregnancy follows a coordinated program of morphological development (formation of lobuloalveoli) and biochemical differentiation (casein production). In culture, whole mammary glands of Balb/c mice can be similarly induced by application of a mixture of insulin, prolactin, aldosterone and hydrocortisone (IPAH) for 7 days. Our previous reports have shown that lobuloalveolar development, induced by IPAH, is competitively inhibited by the simultaneous presence of dibutyryl cyclic AMP (Bt2cAMP), prostaglandins (PGs) E1, E2, and B1, and papaverine (pap). However, if this mixture is not added until day 4, lobuloalveolar development is relatively unaffected but casein synthesis is repressed. This report explores the mechanism by which cyclic adenine nucleotides and prostaglandins interfere with the normal developmental pathway. The accumulation of alpha- and beta-casein mRNAs induced by prolactin, hydrocortisone and aldosterone is blocked by the combination of Bt2cAMP, PGs E1, E2, and B1, and pap added to the medium for the final 3 days (days 4-7). Under these conditions the glands retain their lobuloalveoli, and little squamous metaplasia can be discerned. Furthermore, de novo synthesis of both caseins is selectively inhibited, despite the continued presence of casein mRNAs in the glands and normal protein synthesis. In contrast, the synthesis of keratin is stimulated. Incomplete mixtures of Bt2cAMP and pap or the combination of PGs E1, E2, and B1, are only partly effective in preventing the accumulation of casein mRNAs. All three mixtures bring about similar effects on both alpha- and beta-casein mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS)