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Department of Medicine, Veterans Administration Chicago Healthcare System and Northwestern University Medical School, Chicago, Illinois 60611
Address all correspondence and requests for reprints to: Dr. William L. Lowe, Jr., M.D., Center for Endocrinology, Metabolism, and Molecular Medicine, Tarry 15–703, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: wlowe{at}nwu.edu
The effect of increased intracellular cAMP on MCF-7 breast cancer cell
growth was examined by treating cells with either forskolin, an
activator of adenylate cyclase, or 8-[4-chlorophenylthio]-cAMP
(8-CPT-cAMP), a cAMP analog. Compared to cells maintained in control
medium, treatment with either 1 or 10 µM forskolin
decreased cell growth by 17% and 68%, respectively, whereas treatment
with 250 µM 8-CPT-cAMP decreased cell growth by 29%. To
determine whether this effect of cAMP on cell growth was mediated by
inhibition of the activity of extracellular signal-regulated kinases 1
and 2 (ERK1 and -2), two mitogen-activated protein kinases, the effect
of cAMP on growth factor-induced ERK activity in MCF-7 cells was
examined. Treatment with either insulin-like growth factor I (IGF-I) or
epidermal growth factor (EGF) for 10 min stimulated a 4- to 8-fold
increase in ERK1 and -2 activity. This effect of IGF-I and EGF was not
inhibited by increased intracellular cAMP generated by pretreatment of
the cells with 10 µM forskolin. Similarly, 10
µM forskolin had no effect on IGF-I- or EGF-induced ERK
activity in cells treated with growth factor for 30 min. To determine
whether cAMP inhibits other growth factor-mediated effects, its effect
on the activity of the serum response element (SRE), a DNA promoter
element whose activity is regulated by a variety of growth-promoting
events, was examined. For these assays, MCF-7 cells were transiently
transfected with pTK81-SRE-Luc, a luciferase fusion gene that contains
the SRE cloned 5' to a minimal thymidine kinase promoter and the
luciferase gene. Treatment with either IGF-I or EGF increased
pTK81-SRE-Luc activity in a dose-dependent fashion. Pretreatment of
cells with 10 µM forskolin decreased IGF-I- and
EGF-stimulated luciferase activity by 
75%. An intermediate effect
was observed using 1 µM forskolin. When intracellular
cAMP levels were increased using 8-CPT-cAMP, similar results were
obtained. SRE activity is dependent upon the activation by
phosphorylation of a ternary complex factor; included among the ternary
complex factors is Elk-1. When MCF-7 cells were cotransfected with a
vector that expresses a Gal4/Elk-1 fusion protein and UAS-TK-Luc, a
plasmid that contains two Gal4 DNA recognition sites cloned 5' to a
thymidine kinase promoter and the luciferase gene, treatment with
forskolin partially inhibited the activation of Elk-1 by IGF-I and EGF.
These data demonstrate that in MCF-7 breast cancer cells, cAMP has no
effect on IGF-I- or EGF-induced ERK activity, but it inhibits growth
factor-induced transcription. Taken together with the effects of cAMP
on IGF-I- and EGF-induced Elk-1 activation, these data suggest that the
effect of cAMP on SRE activity occurs distal to ERK activation,
possibly via inhibition of an ERK-independent pathway. Finally, these
data indicate that the effect of increased intracellular cAMP on breast
cancer growth may be mediated through inhibition of specific growth
factor-induced effects, including gene transcription.
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