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Int J Oncol. 2007 Oct;31(4):777-84.

Re-activation of the p53 pathway inhibits in vivo and in vitro growth of hormone-dependent human breast cancer cells.

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1
Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.

Abstract

Mutations in wild-type p53 (wtp53) protein lead to loss of its tumor suppressor function in breast cancer cells, facilitating uncontrolled tumor growth. Consequently, procedures to repair defective p53 functions in tumor cells are being actively pursued. We sought to determine whether expression of wtp53 protein, or conversion of endogenous mutant p53 (mtp53) into a functional p53 protein with small molecule PRIMA-1, can override the tumor-promoting effects of naturally occurring mtp53 protein in hormone-responsive T47-D human breast cancer cells. We show that transfection of wtp53 gene into T47-D cells suppresses their proliferation in regular media, and inhibits estrogen-dependent cell proliferation in media containing dextran-coated charcoal treated serum. Growth inhibition was not due to the absence of estrogen receptor-alpha or estrogen receptor-beta though receptor levels for estrogen receptor-alpha were drastically reduced in wtp53 expressing cells. Focused microarray analysis of wtp53 expressing cells revealed suppression of PCNA cell-cycle regulatory mRNA and protein. Wild-type p53 transfected T47-D cells also failed to grow in vivo in estrogen supplemented nude mice. Furthermore, xenografts obtained with parental T47-D cells expressing mtp53 grew poorly in nude mice treated with PRIMA-1. PRIMA-1 treated tumors exhibited a low proliferation index, even though mice were estrogen-supplemented. PRIMA-1 treatment of tumor cells suppressed VEGF and induced expression of estrogen receptor-beta though expression of estrogen receptor-alpha and progesterone receptors was unaffected. These data indicate that alteration of the p53 signal transduction pathway by re-expression of wtp53 protein in T47-D cells, or treatment of parental cells with PRIMA-1, can prevent in vivo and in vitro proliferation of T47-D breast cancer cells.

PMID:
17786308
[Indexed for MEDLINE]
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