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Endocrinology Vol. 138, No. 9 3891-3900
Copyright © 1997 by The Endocrine Society

ARTICLES

The Epidermal Growth Factor Receptor Is Not Required for Tumor Necrosis Factor-{alpha} Action in Normal Mammary Epithelial Cells1

Linda M. Varela, Kathleen M. Darcy and Margot M. Ip

Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263

Address all correspondence and requests for reprints to: Dr. Margot M. Ip, Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263. E-mail: mip{at}sc3101.med.buffalo.edu

Our laboratory has shown that tumor necrosis factor-{alpha} (TNF{alpha}) can regulate normal mammary epithelial cell (MEC) growth, morphogenesis, and, under certain circumstances, functional differentiation in a manner similar to epidermal growth factor (EGF). As TNF{alpha} has been shown to up-regulate EGF receptor (EGFR) expression and function in other systems, the present studies were undertaken to determine whether TNF{alpha} action in MEC was indirect through stimulation of the EGFR. An inhibitor of EGFR tyrosine kinase activity, PD158780, failed to block proliferation induced by 40 ng/ml TNF{alpha} and only partially inhibited growth in response to 2 ng/ml TNF{alpha}. PD158780 was also unable to suppress the extensive morphological development induced by either TNF{alpha} concentration. In contrast, the effects of TNF{alpha} and PD158780 on functional differentiation (i.e. casein accumulation) were time dependent. When measured on day 7 after 48 h of treatment, casein accumulation was unaffected by either concentration of TNF{alpha} or by PD158780. When assessed on day 21 after 16 days of treatment, however, casein levels were decreased by 40 ng/ml TNF{alpha} and increased by PD158780. Significantly, this PD158780-induced increase in casein was not observed in MEC that had been treated with both PD158780 and TNF{alpha}. These results thus suggest that EGFR tyrosine kinase activity is not necessary for TNF{alpha} action in normal MEC.




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