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Estrogen-dependent and independent activation of the P1 promoter of the p53 gene in transiently transfected breast cancer cells

Oncogene volume 18, pages 1067–1072 (1999)Cite this article

Abstract

Loss of p53 function by mutational inactivation is the most common marker of the cancerous phenotype. Previous studies from our laboratory have demonstrated 17 β estradiol (E2) induction of p53 protein expression in breast cancer cells. Although direct effects of E2 on the expression of p53 gene are not known, the steroid is a potent regulator of c-Myc transcription. In the present studies, we have examined the ability of E2 and antiestrogens to regulate the P1 promoter of the p53 gene which contains a c-Myc responsive element. Estrogen receptor (ER)-positive T47D and MCF-7 cells were transiently transfected with the P1CAT reporter plasmid and levels of CAT activity in response to serum, E2 and antiestrogens were monitored. Factors in serum were noted to be the dominant inducers of chloramphenicol acetyltransferase (CAT) expression in MCF-7 cells. The levels of CAT were drastically reduced when cells were maintained in serum free medium (SFM). However, a subtle ER-mediated induction of CAT expression was detectable when MCF-7 cells, cultured in SFM, were treated with E2. In serum-stimulated T47D cells, the CAT expression was minimal. The full ER antagonist, ICI 182 780 (ICI) had no effect. Treatment with E2 or 4-hydroxy tamoxifen (OHT) resulted in P1CAT induction; OHT was more effective than E2. Consistent with c-Myc regulation of the P1 promoter, E2 stimulated endogenous c-Myc in both cell lines. Two forms of c-Myc were expressed independent of E2 stimuli. The expression of a third more rapidly migrating form was E2-dependent and ER-mediated since it was blocked by the full ER antagonist, ICI, but not by the ER agonist/antagonist OHT. These data demonstrate both ER-mediated and ER-independent regulation of c-Myc and the P1 promoter of the p53 gene, and show differential effects of the two classes of antiestrogens in their ability to induce the P1 promoter of the p53 gene in breast cancer cells.

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Abbreviations

BCS:

bovine calf serum

CAT:

chlomaphenicol acetyltransferase

E2:

17-β estradiol

ECL:

enhanced chemiluminescence

ER:

estrogen receptor

FBS:

fetal bovine serum

ICI:

(ICI 182 780)

OHT:

4-hydroxy tamoxifen

PVDF:

polyvinylidene diflurode

SFM:

serum free medium

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Acknowledgements

The authors are grateful to Dr David Reisman, University of South Carolina, for providing the P1CAT reporter plasmid. The advice and assistance from Drs Janice Schwartz (Wayne State University), Anne Hitt and Jill Zeilstra-Ryalls (Oakland University) are deeply appreciated. The studies were supported in part by the National Institutes of Health (DK 20893) and the Research Excellence Award by the Center for Biomedical Research, Oakland University.

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  1. Department of Biological Sciences and the Center for Biomedical Research, Oakland University, Rochester, 48309-4476, Michigan, USA

    Cliff Hurd, Sumi Dinda, Nidhi Khattree & V K Moudgil

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Hurd, C., Dinda, S., Khattree, N. et al. Estrogen-dependent and independent activation of the P1 promoter of the p53 gene in transiently transfected breast cancer cells. Oncogene 18, 1067–1072 (1999). https://doi.org/10.1038/sj.onc.1202398

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