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J Biol Chem, Vol. 273, Issue 46, 30608-30613, November 13, 1998
From the The molecular signaling events involved in the
inhibition of breast cancer cell growth by retinoic acid and
interferon-
c-Myc Is a Major Mediator of the Synergistic Growth Inhibitory
Effects of Retinoic Acid and Interferon in Breast Cancer Cells
,
Nutrition Department and the
§ Department of Dairy and Animal Science, Pennsylvania State
University, University Park, Pennsylvania 16802
were investigated. All-trans-retinoic acid
and interferon-
acted synergistically to inhibit growth of both the
estrogen receptor-positive breast cancer cell line MCF-7 and the
estrogen receptor-negative line BT-20. In MCF-7 cells,
all-trans-retinoic acid potentiated the effects of
interferon-
by up-regulating the expression of the RNA-dependent protein kinase (PKR). Consequently, the
synergism between all-trans-retinoic acid and
interferon-
down-regulated the expression of c-Myc, but not its
functional partner, Max. Transfection of MCF-7 cells with a
dominant-negative mutant of PKR relieved c-Myc down-regulation and cell
growth inhibition, indicating that PKR is directly involved in c-Myc
down-regulation and that c-Myc down-regulation is responsible for the
inhibition of cell growth. Corresponding with c-Myc down-regulation,
c-Myc·Max heterodimers bound to their consensus DNA sequence were
undetectable in cells treated with all-trans-retinoic acid
and interferon-
, indicating diminished c-Myc functionality. When
c-Myc was overexpressed ectopically via a c-Myc expression vector,
MCF-7 cells became resistant to growth inhibition by
all-trans-retinoic acid plus interferon-
. These
experiments define the following pathway as a major pathway in the
synergistic growth inhibition of MCF-7 cells by
all-trans-retinoic acid plus interferon-
:
all-trans-retinoic acid + interferon-
double-stranded RNA-dependent protein kinase
c-Myc
cell growth inhibition.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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