Originally published as JCO Early Release 10.1200/JCO.2005.01.172 on March 7 2005

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Molecular Changes in Tamoxifen-Resistant Breast Cancer: Relationship Between Estrogen Receptor, HER-2, and p38 Mitogen-Activated Protein Kinase

M. Carolina Gutierrez, Simone Detre, Stephen Johnston, Syed K. Mohsin, Jiang Shou, D. Craig Allred, Rachel Schiff, C. Kent Osborne, Mitch Dowsett

From the Breast Center and Departments of Pathology and Medicine, Baylor College of Medicine, Houston, TX; and Academic Department of Biochemistry and Breast Unit, Royal Marsden Hospital, London, United Kingdom

Address reprint requests to Mitch Dowsett, MD, Academic Department of Biochemistry, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom; e-mail: mitch.dowsett{at}rmh.nthames.nhs.uk.

PURPOSE: To evaluate growth factor receptor cross talk with the estrogen receptor (ER) in paired clinical breast cancer specimens and in a xenograft model before tamoxifen and at tumor progression as a possible mechanism for tamoxifen resistance.

METHODS: Specimen pairs from 39 patients were tissue arrayed and stained for ER, progesterone receptor (PgR), Bcl-2, c-ErbB2 (HER-2), and phosphorylated (p) p38 mitogen-activated protein kinase (MAPK), p-ERK1/2 MAPK, and p-Akt. Xenograft MCF-7 tumors before and after tamoxifen resistance were assessed for levels of p-p38.

RESULTS: Pretreatment, there were strong correlations between ER, PgR, and Bcl-2, and an inverse correlation between ER and HER-2. These correlations were lost in the tamoxifen- resistant tumors and replaced by strong correlations between ER and p-p38 and p-ERK. ER expression was lost in 17% of resistant tumors. Three (11%) of the 26 tumors originally negative for HER-2 became amplified and/or overexpressed at resistance. All ER-positive tumors that overexpressed HER-2 originally or at resistance expressed high levels of p-p38. In the pretreatment and tamoxifen-resistant specimens, there were strong correlations between p-p38 and p-ERK. In the tamoxifen-resistant xenograft tumors, like the clinical samples, there was a striking increase in p-p38.

CONCLUSION: The molecular pathways driving tumor growth can change as the tumor progresses. Crosstalk between ER, HER-2, p38, and ERK may contribute to tamoxifen resistance and may provide molecular targets to overcome this resistance.

Funded in part by Breast Cancer Specialized Program of Research Excellence Grant P50 CA58183 and by the Royal Marsden Charity.

Drs Gutierrez and Dowsett contributed equally to this manuscript.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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