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This Article Accepted manuscript (PDF) Supplementary figure All Versions of this Article: JME-08-0026v1 41/5/367    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Chen, B. Articles by Chen, S. PubMed PubMed Citation Articles by Chen, B. Articles by Chen, S.

B Chen, Department of Surgical Research, Beckman Research Institute of City of Hope, Duarte, United States
Y Wang, Department of Surgical Research, Beckman Research Institute of City of Hope,, Duarte, United States
S Kane, Division of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, United States
S Chen, Department of Surgical Research, Beckman Research Institute of City of Hope, Duarte, United States

Correspondence: Bin Chen, Email: binnchen{at}tom.com

Abstract

Her2 overexpression in ER-positive breast cancer cells such as BT474 (BT) cells has been found to confer resistance to tamoxifen, and suppression of Her2 improves the antiproliferative effects of tamoxifen. In this study, the responsiveness to tamoxifen in BT/HerR, Herceptin-resistant BT cell lines established through constant Herceptin exposure, was evaluated. Compared with BT cells, improvement of sensitivity to tamoxifen in BT/HerR was demonstrated by ER functional analysis and cell proliferation assay. Tamoxifen in the resistant cell line was found to inhibit E2-stimulating estrogen-responsive gene pS2 expression more effectively than in BT cells in real time PCR assay. Western analysis showed cross-phosphorylation between ER and downstream components of Her2 was attenuated in BT/HerR cells. ER redistribution from cytoplasm to nucleus could be found in these cells through immunofluorescence and confocal studies and importantly, chromatin immunoprecipitation (ChIP) studies demonstrated that tamoxifen induced occupancy of the pS2 promoter by ER and nuclear receptor corepressor NCoR instead of coactivator AIB1 in these cells. Finally, combination of tamoxifen and Herceptin was found to improve the sensitivity of BT/HerR cells to Herceptin. Our results suggest that the ER genomic pathway in the ER-positive and Herceptin-resistant breast cancer cells may be reactivated, allowing tamoxifen therapy to be effective again, and a combination of tamoxifen and Herceptin can be a potential therapeutic strategy for ER-positive and Herceptin-resistant human breast cancer.