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Submitted on June 5, 2003
Accepted on July 29, 2003
1 Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff; AstraZeneca, Macclesfield, UK.
* To whom correspondence should be addressed. E-mail: gee{at}cardiff.ac.uk.
While many ER positive breast cancers initially respond to anti-hormones, responses are commonly incomplete with resistance ultimately emerging. Delineation of signaling mechanisms underlying these phenomena would allow development of therapies to improve anti-hormone response and compromise resistance. This in vitro investigation in MCF-7 breast cancer cells examines whether epidermal growth factor receptor (EGFR) signaling limits anti-proliferative and pro-apoptotic activity of anti-hormones and ultimately supports development of resistance. It addresses whether the anti-EGFR agent gefitinib (ZD1839/IressaTM; TKI: 1 µM) combined with the anti-hormones 4-hydroxytamoxifen (TAM: 0.1 µM) or fulvestrant (FaslodexTM; FAS: 0.1 µM) enhances growth inhibition and prevents resistance. TAM significantly suppressed MCF-7 growth over Weeks 2-5, reducing proliferation detected by immunocytochemistry and FACS cell cycle analysis. A modest apoptotic increase was observed by FACS and fluorescence microscopy, with incomplete bcl-2 suppression. EGFR induction occurred during TAM response, as measured by immunocytochemistry and Western blotting, with EGFR positive, highly proliferative resistant growth subsequently emerging. While TKI alone was ineffective on growth, TAM plus TKI co-treatment exhibited superior anti-growth activity vs. TAM, with no viable cells by Week 12. Co-treatment was more effective in inhibiting proliferation, promoting apoptosis and eliminating bcl-2. Co-treatment blocked EGFR induction, markedly depleted ERK1/2 MAPK and AKT phosphorylation and prevented emergence of EGFR positive resistance. FAS plus TKI co-treatment was also a superior anti-tumor strategy. Thus, increased EGFR evolves during treatment with anti-hormones, limiting their efficacy and promoting resistance. Gefitinib addition to anti-hormonal therapy could prove more effective in treating ER positive breast cancer and may combat development of resistance.
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