Repression of the insulin receptor promoter by the tumor suppressor gene product
p53: a possible mechanism for receptor overexpression in breast cancer.

Webster NJ, Resnik JL, Reichart DB, Strauss B, Haas M, Seely BL

Department of Medicine, Division of Endocrinology and Metabolism, University of
California, San Diego, La Jolla, California 92093, USA.

There is strong evidence to suggest that insulin and insulin-like growth factor
(IGF)-I may be important for tumor growth. Both the insulin and IGF-I receptors
(IGF-IR) are overexpressed in breast cancer, and antibody blockade of the IGF-IR
inhibits the growth of some breast cancer cell lines. Furthermore, expression of
an insulin receptor (IR) in a normal mammary epithelia] cell line causes
insulin-dependent transformation. Functional inactivation of p53 is also very
frequent in many tumors. In this paper, we investigated whether inactivation of
p53 might be involved in the overexpression of the IR in malignancy,
specifically breast cancer. We demonstrate a positive correlation between IR and
IGF-IR levels and p53 overexpression in primary human breast malignancies. To
examine possible mechanisms by which p53 may regulate IR gene expression, we
show that p53 can repress the IR promoter and that a dominant-negative p53
(248Q) can de-repress the promoter in cells containing normal p53. The p53
effect was shown to be mediated by C/EBP and Sp1 transcription factors. We also
documented that p53-null mice had elevated levels of Sp1, but not C/EBPalpha,
and that insulin binding to liver extracts was increased compared to wild-type
controls. These results suggest that p53 inactivation may lead to an
up-regulation of genes, such as the IR, that are dependent on these
transcription factors.

MeSH Terms:
Animal
Base Sequence
Binding, Competitive
Breast Neoplasms/metabolism*
DNA-Binding Proteins/metabolism*
Female
Genes, Reporter
Human
Insulin/metabolism*
Insulin-Like Growth Factor I/metabolism*
Mice
Molecular Sequence Data
Nuclear Proteins/metabolism*
Promoter Regions (Genetics)*
Protein p53/physiology
Protein p53/metabolism*
Protein p53/deficiency
Receptor, Insulin/metabolism*
Receptor, Insulin/genetics
Receptor, IGF Type 1/metabolism*
Support, Non-U.S. Gov't
Support, U.S. Gov't, Non-P.H.S.
Support, U.S. Gov't, P.H.S.
Transcription Factor, Sp1/metabolism*
Transfection

Substances:
Insulin-Like Growth Factor I
Insulin
Transcription Factor, Sp1
Protein p53
Nuclear Proteins
DNA-Binding Proteins
C-EBP nuclear protein
Receptor, IGF Type 1
Receptor, Insulin

Grant support:
DK 44643/DK/NIDDK
DK 02162/DK/NIDDK

PMID: 8665514, UI: 96275749