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Action in Normal Mammary Epithelial Cells1
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-
(TNF
) 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
has been
shown to up-regulate EGF receptor (EGFR) expression and function in
other systems, the present studies were undertaken to determine whether
TNF
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
and only partially inhibited
growth in response to 2 ng/ml TNF
. PD158780 was also unable to
suppress the extensive morphological development induced by either
TNF
concentration. In contrast, the effects of TNF
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
or by PD158780. When assessed on day 21 after 16 days of
treatment, however, casein levels were decreased by 40 ng/ml TNF
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
. These results thus suggest that EGFR tyrosine kinase
activity is not necessary for TNF
action in normal MEC.
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