GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis

  • Authors:
    • Heng Yin
    • Qing Zhu
    • Manran Liu
    • Gang Tu
    • Qing Li
    • Jie Yuan
    • Siyang Wen
    • Guanglun Yang
  • View Affiliations

  • Published online on: September 5, 2017     https://doi.org/10.3892/ijo.2017.4117
  • Pages:1191-1198
0

Abstract

Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Our previous studies find that GPER and its down-stream signaling play a pivotal role in the development of tamoxifen (TAM) resistance. cDNA array analysis indicated a set of genes associated with cell apoptosis are aberrant in GPER activated and TAM-resistant MCF-7R cells compared with TAM-sensitive MCF-7 cells. Among these genes, Bim (also named BCL2-L11), a member of the BH3-only pro-apoptotic protein family is significantly decreased, and TRIM RING finger protein TRIM2 (a ubiquitin ligase) is highly expressed in MCF-7R. To understand the mechanism of TAM-resistance in GPER activated ER+ breast cancer, the function of TRIM2 and Bim inducing cell apoptosis was studied. By using immunohistochemical and western blot analysis, there is an adverse correlation between TRIM2 and Bim in TAM-resistant breast tumor tissues and MCF-7R cells. Knockdown Bim in TAM-sensitive MCF-7 cells or overexpression of Bim in TAM-resistant MCF-7 cells significantly changed its sensibility to TAM through altering the levels of cleaved PARP and caspase-3. Activation of GPER and its downstream signaling MAPK/ERK, not PI3K/AKT, led to enhanced TRIM2 protein levels and affected the binding between TRIM2 and Bim which resulted in a reduced Bim in TAM-resistant breast cancer cells. Thus, the present study provides a novel insight to TAM-resistance in ER-positive breast cancer cells.

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October 2017
Volume 51 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

2016 Impact Factor: 3.079
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APA
Yin, H., Zhu, Q., Liu, M., Tu, G., Li, Q., Yuan, J. ... Yang, G. (2017). GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis. International Journal of Oncology, 51, 1191-1198. https://doi.org/10.3892/ijo.2017.4117
MLA
Yin, H., Zhu, Q., Liu, M., Tu, G., Li, Q., Yuan, J., Wen, S., Yang, G."GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis". International Journal of Oncology 51.4 (2017): 1191-1198.
Chicago
Yin, H., Zhu, Q., Liu, M., Tu, G., Li, Q., Yuan, J., Wen, S., Yang, G."GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis". International Journal of Oncology 51, no. 4 (2017): 1191-1198. https://doi.org/10.3892/ijo.2017.4117