Effects of phorbol esters on multiplication and differentiation of mammary cells

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Abstract
Three phorbol esters: phorbol-12,13-dibutyrate (PDB), 12-O-tetradecanoylphorbol-13-acetate (TPA) and phorbol-12,13-diacetate (PDA) were added at various concentrations (101-104 ng/ml) to the culture medium of rabbit mammary explants. The 3 phorbol esters inhibited the mitogenic signals of insulin, EGF [epidermal growth factor] and prolactin. They also prevented the induction of casein synthesis and casein mRNA accumulation by prolactin. In all cases, the most potent inhibitor was PDB. PDB did not alter the binding of prolactin to its receptors. The 3 phorbol esters added to mammary cell membranes with prolactin prevented the generation of the hormonal relay which specifically stimulates casein gene transcription when added to isolated nuclei. Apparently, phorbol esters act directly at the membrane level where they interrupt the transfer of the hormonal messages, through a mechanism which may not be related to their promoter potency.