Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 22, No 14S (July 15 Supplement), 2004: 541
© 2004 American Society of Clinical Oncology

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Abstract

Tamoxifen's agonist effect on breast cancer growth is mediated by activation of EGFR/HER-2 with preservation of its antagonist effect on ER-dependent gene expression

Baylor College of Medicine, Houston, TX; Astra Zeneca, Macclesfield, United Kingdom

541

Background: Tamoxifen (TAM) is an estrogen receptor (ER) modulator that has both agonist and antagonist properties depending on the molecular profile of its target. We have shown that when HER-2 is overexpressed in MCF-7 tumors, TAM becomes a de novo estrogen-like agonist while fulvestrant (FUL) and estrogen deprivation (ED) remain effective endocrine therapies. Methods: To determine if this TAM agonist effect is mediated by classical ER-regulated transcription activation or by non-classical activity through growth factor pathways, we studied expression of ER-dependent genes and HER-2 signaling elements using western blot analysis. Results: TAM-stimulated MCF-7/HER-2 tumors, which express ER, had reduced levels of ER-dependent genes, just like tumors regressing on ED or FUL. In contrast, levels of p-HER-2 and p-MAPK were elevated in the TAM-stimulated tumors and control E2-stimulated tumors, but were markedly reduced in the ED and FUL-treated tumors, suggesting that activation of HER-2 mediates the de novo agonist effect of TAM. Interestingly, in wild type MCF-7 tumors which acquire TAM-stimulated growth after long-term treatment, TAM also remains an effective antagonist on ER-dependent genes, but EGFR increases markedly at the time of resistance, suggesting that EGFR mediates the acquired agonist effect of TAM. Next, we proceeded to treat mice bearing MCF-7/HER-2 tumors with ED, TAM, or FUL either in the presence or in the absence of E2. While TAM stimulated growth in ED mice, it inhibited E2-stimulated tumor growth. FUL inhibited E2-stimulated growth, but in contrast to TAM, its antitumor effect was greater in ED mice, probably because FUL has no known agonist activity of its own. Conclusions: In this breast cancer model, TAM agonist effects are mediated by EGFR/HER-2, but it remains an effective antagonist on at least some classical ER-dependent transcription activation functions. The data suggest that the use of growth factor pathway inhibitors may improve TAM benefit by eliminating its agonist effect, and that ED may further improve the antitumor effect of FUL but not that of TAM.

Author Disclosure

Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca

Abstract presentation from the 2004 ASCO Annual Meeting