In the present study we have evaluated the effect of recombinant interferons, including leukocyte (IFN-alpha A), fibroblast (IFN-beta) and immune (IFN-gamma), and the tumor promoting agent 12-0-tetradecanoyl-phorbol-13-acetate (TPA) on the expression of tumor associated antigens (TAA) and class II HLA-DR antigens on human breast carcinoma cell lines. The effect of these agents on the shedding of a high molecular weight tumor associated glycoprotein, BCA-225, was also determined. All three interferons and TPA enhanced the expression of the Mr 180,000 carcinoembryonic antigen (CEA) and CEA-related TAA recognized by monoclonal antibody B1.1 in both T47D and MCF-7 human breast carcinoma cell lines. The three types of interferons and TPA differed in their absolute TAA-augmenting ability, even in single-cell subclones derived from MCF-7 cells and previously shown to display a differential susceptibility to IFN-alpha augmentation of B1.1 expression. In general, IFN-gamma was more effective than IFN-alpha, IFN-beta or TPA in augmenting the expression of TAA, CEA and BCA-225, and HLA-DR expression in T47D and MCF-7 cells. Differences were also apparent in the ability of the three interferon preparations and TPA to induce shedding of BCA-225 in T47D and MCF-7 cells and their subclones. As observed with TAA expression, IFN-gamma was the most effective preparation in inducing TAA shedding. IFN-gamma also induced the expression and the shedding of BCA-225 by a subclone of T47D cells, T47D cl 17, which normally displays a reduced expression of BCA-225 and does not spontaneously shed this TAA without exposure to IFN-gamma. Recombinant leukocyte interferon (IFN-alpha A) also enhanced BCA-225 expression on T47D cells grown as xenografts in nude mice in vivo. The results of the present study emphasize the complexity of potential antigenic responses which can be induced in human breast carcinoma cells when they are exposed to biological response modulators, including different types of interferon, and tumor promoting agents, such as TPA. This investigation also indicates that both classes of agents can differentially augment expression and/or shedding of TAA by specific breast carcinoma cell lines as well as subclones derived from the same breast carcinoma cell line.