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Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University School of Medicine, Washington, District Columbia

Requests for reprints: Robert Clarke, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Room W405A Research Building, 3970 Reservoir Road Northwest, Washington, DC 20057. Phone: 202-687-3755; Fax: 202-687-7505. E-mail: clarker{at}georgetown.edu.

The molecular mechanisms underlying the acquisition of resistance to the antiestrogen Faslodex are poorly understood, although enhanced expression and activity of nuclear factor B (NFB) have been implicated as a critical element of this phenotype. The purpose of this study was to elucidate the mechanism by which NFB up-regulation contributes to Faslodex resistance and to determine whether pharmacologic inhibition of NFB by the small molecule parthenolide could restore Faslodex-mediated suppression of cell growth. Basal expression of multiple NFB-related molecules in MCF7-derived LCC1 (antiestrogen-sensitive) and LCC9 (antiestrogen-resistant) breast cancer cells was determined, and cells were treated with Faslodex or parthenolide. The effect of these drugs either singly or in combination was assessed by cell proliferation, estrogen receptor (ER)–dependent transcriptional activation, cell cycle analysis, and apoptosis assays. Expression of the p65 NFB subunit and the upstream NFB regulator IB kinase /NFB essential modulator were increased in the resistant MCF7/LCC9 cells (P = 0.001 and 0.04, respectively). Whereas MCF7/LCC9 cells were unresponsive to Faslodex alone, parthenolide effectively inhibited MCF7/LCC9 cell proliferation and the combination of Faslodex and parthenolide resulted in a 4-fold synergistic reduction in cell growth (P = 0.03). This corresponded to a restoration of Faslodex-induced apoptosis (P = 0.001), with no observable changes in ER-dependent transcription or cell cycle phase distribution. Because parthenolide has shown safety in Phase I clinical trials, these findings have direct clinical relevance and provide support for the design of clinical studies combining antiestrogens and parthenolide in ER-positive breast cancer.

Key Words: NFB • Faslodex • parthenolide • cell cycle • proliferation • apoptosis • breast cancer

Grant support: Public Health Service awards R01-CA/AG58022-10 (R. Clarke); Institutional Training grant T32A09686 (Georgetown University; R. Riggins); Department of Defense awards BC031348 (R. Nehra), BC010619, and BC990358 (R. Clarke) from the United States Army Medical Research and Materiel Command; technical services provided by the Flow Cytometry and Cell Sorting and Microscopy and Imaging Shared Resources funded through Public Health Service awards 2P30-CA-51008 and 1S10 RR15768-01 (Lombardi Comprehensive Cancer Center support grant).

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.

Received 8/ 4/04; revised 10/28/04; accepted 11/10/04.

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