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Cooperation of TGFα and c-Myc in mouse mammary tumorigenesis: Coordinated stimulation of growth and suppression of apoptosis

par Amundadottir, Laufey Thora;Nass, Sharyl S.J.;Berchem, Guy ;Johnson, Michael D L M.D.;Dickson, Robert R.B.
Référence Oncogene, 13, 4, page (757-765)
Publication Publié, 1996

Article révisé par les pairs

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Résumé :

We have previously shown that TGFα 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 TGFα-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 TGFα transgene, indicating that TGFα 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 TGFα transgene. Furthermore, exogenous addition of TGFα inhibited apoptosis in cells overexpressing c-Myc alone. In addition, tumor-derived cells that overexpressed both TGFα and c-Myc exhibited faster growth rates in vitro and in vivo and were less sensitive to the inhibitory effects of TGFβ in vitro compared to cell lines expressing only one of the transgenes. Based on our findings we propose that TGFα acts both as a proliferative and a survival factor for c-Myc-expressing tumor cells. Our results indicate that TGFα and c-Myc cooperate in tumorigenesis via a dual mechanism: TGFα can inhibit c-Myc-induced apoptosis and both proteins provide a growth stimulus.