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Research Articles: Therapeutics, Targets, and Development

Apigenin inhibits antiestrogen-resistant breast cancer cell growth through estrogen receptor--dependent and estrogen receptor--independent mechanisms

¹ Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana; ² Department of Pathology, University of Tennessee-Memphis, Memphis, Tennessee; and Departments of ³ Obstetrics and Gynecology and ⁴ Cellular and Integrative Physiology and ⁵ Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana

Requests for reprints: Kenneth P. Nephew, Medical Sciences, Indiana University School of Medicine, 302 Jordan Hall, 1001 East 3rd Street, Bloomington, IN 47405-4401. Phone: 812-855-9445; Fax: 812-855-4436. E-mail: knephew{at}indiana.edu

Abstract

Breast cancer resistance to the antiestrogens tamoxifen (OHT) and fulvestrant is accompanied by alterations in both estrogen-dependent and estrogen-independent signaling pathways. Consequently, effective inhibition of both pathways may be necessary to block proliferation of antiestrogen-resistant breast cancer cells. In this study, we examined the effects of apigenin, a dietary plant flavonoid with potential anticancer properties, on estrogen-responsive, antiestrogen-sensitive MCF7 breast cancer cells and two MCF7 sublines with acquired resistance to either OHT or fulvestrant. We found that apigenin can function as both an estrogen and an antiestrogen in a dose-dependent manner. At low concentrations (1 µmol/L), apigenin stimulated MCF7 cell growth but had no effect on the antiestrogen-resistant MCF7 sublines. In contrast, at high concentrations (>10 µmol/L), the drug inhibited growth of MCF7 cells and the antiestrogen-resistant sublines, and the combination of apigenin with either OHT or fulvestrant showed synergistic, growth-inhibitory effects on both antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. To further elucidate the molecular mechanism of apigenin as either an estrogen or an antiestrogen, effects of the drug on estrogen receptor- (ER); transactivation activity, mobility, stability, and ER-coactivator interactions were investigated. Low-dose apigenin enhanced receptor transcriptional activity by promoting interaction between ER and its coactivator amplified in breast cancer-1. However, higher doses (>10 µmol/L) of apigenin inhibited ER mobility (as determined by fluorescence recovery after photobleaching assays), down-regulated ER and amplified in breast cancer-1 expression levels, and inhibited multiple protein kinases, including p38, protein kinase A, mitogen-activated protein kinase, and AKT. Collectively, these results show that apigenin can function as both an antiestrogen and a protein kinase inhibitor with activity against breast cancer cells with acquired resistance to OHT or fulvestrant. We conclude that apigenin, through its ability to target both ER-dependent and ER-independent pathways, holds promise as a new therapeutic agent against antiestrogen-resistant breast cancer. [Mol Cancer Ther 2008;7(7):2096–108]

Grant support: NIH/National Cancer Institute grants CA 085289 and CA 113001, U.S. Army Medical Research Acquisition Activity awards DAMD 17-02-1-0418 and DAMD 17-02-1-0419, American Cancer Society Research and Alaska Run for Woman grant TBE-104125, and Walther Cancer Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 11/30/07; revised 3/10/08; accepted 3/18/08.