ROLE FOR BCL-X(L) IN THE REGULATION OF APOPTOSIS BY EGF AND TGF-BETA-1 IN C-MYC OVEREXPRESSING MAMMARY EPITHELIAL-CELLS

We previously showed that TGF alpha synergizes with c-myc in mammary t umorigenesis through inhibition of Myc-induced apoptosis. We therefore examined the effects of growth factors on apoptosis induction in seve ral cell lines from MMTV-myc mammary tumors. When EGF was withdrawn or TGF beta 1 was added, cells became apoptotic after 15 h (by ELISA and morphology). Northern and Western analysis revealed high levels of Ba r and p53, and low or undetectable levels of Bcl-2 and Bcl-x(S) under all treatment conditions. In contrast, Bcl-x(L) expression was highest in the presence of EGF or TGF alpha, with a significant reduction upo n removal of EGF or exposure to TGF beta. In mouse mammary tumors, the relative Bcl-x(L)/Bax ratio was higher in TGF alpha/Myc double transg enics than in Myc single transgenics, in agreement with the in vitro d ata. Our results suggest a role for Bcl-x(L) in the regulation of apop tosis by EGF and TGF beta in mammary epithelial cells. (C) 1996 Academ ic Press, Inc.