Cooperation of TGF alpha and c-Myc in mouse mammary tumorigenesis: coordinated stimulation of growth and suppression of apoptosis.

We have previously shown that TGF alpha and c-Myc interact in a strong, synergistic fashion to induce mammary gland tumors in double transgenic mice. Here we show this interaction can be explained, at least in part, by a cooperative growth stimulus by the two proteins, and by TGF alpha-mediated inhibition of c-Myc-induced apoptosis. We initially compared rapidly progressing mammary tumors from double transgenic mice to long latency tumors from single transgenic mice and observed a striking difference in the occurrence of apoptosis among the three groups. Tumors exhibiting apoptosis were derived exclusively from mice that expressed the c-myc transgene in the absence of the TGF alpha transgene, indicating that TGF alpha might protect c-Myc-overexpressing cells from programmed cell death. Cell lines were derived from single and double transgenic mammary tumors to examine further the mechanism underlying the cooperative interaction between the two gene products. In accordance with our in vivo data, apoptosis was only detected when the c-myc transgene was expressed without the TGF alpha transgene. Furthermore, exogenous addition of TGF alpha inhibited apoptosis in cells overexpressing c-Myc alone. In addition, tumor-derived cells that overexpressed both TGF alpha and c-Myc exhibited faster growth rates in vitro and in vivo and were less sensitive to the inhibitory effects of TGF beta in vitro compared to cell lines expressing only one of the transgenes. Based on our findings we propose that TGF alpha acts both as a proliferative and a survival factor for c-Myc-expressing tumor cells. Our results indicate that TGF alpha and c-Myc cooperate in tumorigenesis via a dual mechanism: TGF alpha can inhibit c-Myc-induced apoptosis and both proteins provide a growth stimulus.