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01-09-2015 | Research Article

ObRb downregulation increases breast cancer cell sensitivity to tamoxifen

Authors: Yingying Qian, Dongmin Shi, Jinrong Qiu, Fang Zhu, Jing Qian, Shaohua He, Yongqian Shu, Yongmei Yin, Xiaofeng Chen

Published in: Tumor Biology | Issue 9/2015

Abstract

Leptin is a potent adipokine that plays an important role in the progression of breast cancer and interferes with the action of tamoxifen. We investigated the molecular mechanism underlying the effect of leptin on tamoxifen resistance in breast cancer cells that express leptin receptor (ObRb), and evaluated the impact of ObRb suppression on tamoxifen treatment in MCF-7 and tamoxifen-resistant (TAM-R) cells. Leptin-induced signaling pathway activation was examined by qRT-PCR and Western blotting. Chromatin immunoprecipitation assays were performed to further examine the binding of estrogen receptor (ER) α on the promoter of cyclin D1 (CCND1) gene. The effects of combined ObRb knockdown and tamoxifen treatment were evaluated in MCF-7 and TAM-R cells. We found that the enhanced proliferation effects induced by leptin were related to extracellular-signal-regulated kinase (ERK) 1/2 and signal transducers and activators of transcription (STAT) 3 signaling pathway activation and CCND1 upregulation. Leptin enhanced CCND1 gene transcription by inducing the binding of ERα to the promoter of CCND1 gene. ObRb knockdown significantly enhanced the inhibitory effects of tamoxifen on TAM-R cell proliferation and survival. This study suggested that long-term endocrine therapy facilitates leptin and ObRb overexpression in breast cancer cells, which attenuates the inhibitory effect of tamoxifen by activating both the ERK1/2 and STAT3 signaling pathways and upregulating CCND1 gene expression. Combination therapy involving ObRb knockdown and tamoxifen treatment may be an alternative therapeutic option for tamoxifen-resistant breast cancer.

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Title: ObRb downregulation increases breast cancer cell sensitivity to tamoxifen
Authors: Yingying Qian
Dongmin Shi
Jinrong Qiu
Fang Zhu
Jing Qian
Shaohua He
Yongqian Shu
Yongmei Yin
Xiaofeng Chen
Publication date: 01-09-2015
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 9/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-3375-5

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