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Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells.
Breast Cancer Res Treat. 2012 Dec; 136(3):739-48.BC

Abstract

Resistance to trastuzumab is a major issue in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Several potential resistance mechanisms have been investigated, but the results are controversial and no conclusion has been reached. Erythropoietin receptor (EPOR) may function in cell growth, and expressed in various cancer cells. Because the downstream signaling pathways for EPOR and HER2 partially overlapped, we hypothesized that EPOR may play a role in the inhibition effect of trastuzumab and resistance to trastuzumab. Here, we detected the expression of EPOR mRNA and protein in HER2-positive breast cancer cell lines and tissues. EPOR expressed in SKBR3, MDA-MB-453, and UACC-812 cell lines, but not in BT474. Of the 55 HER2-positive cancer tissues, EPOR was positive in 42 samples and highly expressed (H-score ≥ 25) in 24 by immunohistochemistry. The difference between EPOR expression and Ki67 index was significant (P = 0.033), and EPOR expression also positively correlated with higher pathological stage (Spearman correlation coefficient = 0.359; P = 0.007). Exogenous EPO antagonized trastuzumab-induced inhibition of cell proliferation in HER2/EPOR dual-positive breast cancer cells. We then exposed SKBR3 cells to trastuzumab for 4 months to obtain trastuzumab-resistant SKBR3 cell line, which demonstrated higher phosphorylated EPOR level, higher EPO expression and more extracellular secretion than non-resistant parental SKBR3 cells. Downregulation EPOR expression using short hairpin RNA resensitized trastuzumab-resistant cells to this drug, and SKBR3 cells with EPOR downregulation demonstrated attenuated trastuzumab resistance after the same resistance induction. EPOR downregulation plus trastuzumab produced a synergetic action in the inhibition of cell proliferation and invasion in SKBR3 and MDA-MB-453 cell lines. Therefore, EPOR expression may be involved in tumor progression and proliferation in HER2-positive breast cancer. EPO/EPOR contributes to the mechanism of trastuzumab resistance in SKBR3 cell lines, and EPOR downregulation can reverse the resistance to trastuzumab and increase the inhibition effect of this drug.

Authors+Show Affiliations

Peking University First Hospital Breast Disease Centre, Xishiku Street 8#, Xicheng District, Beijing, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23117856

Citation

Zhang, Chi, et al. "Erythropoietin Receptor Expression and Its Relationship With Trastuzumab Response and Resistance in HER2-positive Breast Cancer Cells." Breast Cancer Research and Treatment, vol. 136, no. 3, 2012, pp. 739-48.
Zhang C, Duan X, Xu L, et al. Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells. Breast Cancer Res Treat. 2012;136(3):739-48.
Zhang, C., Duan, X., Xu, L., Ye, J., Zhao, J., & Liu, Y. (2012). Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells. Breast Cancer Research and Treatment, 136(3), 739-48. https://doi.org/10.1007/s10549-012-2316-x
Zhang C, et al. Erythropoietin Receptor Expression and Its Relationship With Trastuzumab Response and Resistance in HER2-positive Breast Cancer Cells. Breast Cancer Res Treat. 2012;136(3):739-48. PubMed PMID: 23117856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells. AU - Zhang,Chi, AU - Duan,Xuening, AU - Xu,Ling, AU - Ye,Jingming, AU - Zhao,Jianxin, AU - Liu,Yinhua, Y1 - 2012/11/02/ PY - 2012/09/08/received PY - 2012/10/25/accepted PY - 2012/11/3/entrez PY - 2012/11/3/pubmed PY - 2013/6/12/medline SP - 739 EP - 48 JF - Breast cancer research and treatment JO - Breast Cancer Res Treat VL - 136 IS - 3 N2 - Resistance to trastuzumab is a major issue in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Several potential resistance mechanisms have been investigated, but the results are controversial and no conclusion has been reached. Erythropoietin receptor (EPOR) may function in cell growth, and expressed in various cancer cells. Because the downstream signaling pathways for EPOR and HER2 partially overlapped, we hypothesized that EPOR may play a role in the inhibition effect of trastuzumab and resistance to trastuzumab. Here, we detected the expression of EPOR mRNA and protein in HER2-positive breast cancer cell lines and tissues. EPOR expressed in SKBR3, MDA-MB-453, and UACC-812 cell lines, but not in BT474. Of the 55 HER2-positive cancer tissues, EPOR was positive in 42 samples and highly expressed (H-score ≥ 25) in 24 by immunohistochemistry. The difference between EPOR expression and Ki67 index was significant (P = 0.033), and EPOR expression also positively correlated with higher pathological stage (Spearman correlation coefficient = 0.359; P = 0.007). Exogenous EPO antagonized trastuzumab-induced inhibition of cell proliferation in HER2/EPOR dual-positive breast cancer cells. We then exposed SKBR3 cells to trastuzumab for 4 months to obtain trastuzumab-resistant SKBR3 cell line, which demonstrated higher phosphorylated EPOR level, higher EPO expression and more extracellular secretion than non-resistant parental SKBR3 cells. Downregulation EPOR expression using short hairpin RNA resensitized trastuzumab-resistant cells to this drug, and SKBR3 cells with EPOR downregulation demonstrated attenuated trastuzumab resistance after the same resistance induction. EPOR downregulation plus trastuzumab produced a synergetic action in the inhibition of cell proliferation and invasion in SKBR3 and MDA-MB-453 cell lines. Therefore, EPOR expression may be involved in tumor progression and proliferation in HER2-positive breast cancer. EPO/EPOR contributes to the mechanism of trastuzumab resistance in SKBR3 cell lines, and EPOR downregulation can reverse the resistance to trastuzumab and increase the inhibition effect of this drug. SN - 1573-7217 UR - https://www.unboundmedicine.com/medline/citation/23117856/Erythropoietin_receptor_expression_and_its_relationship_with_trastuzumab_response_and_resistance_in_HER2_positive_breast_cancer_cells_ L2 - https://doi.org/10.1007/s10549-012-2316-x DB - PRIME DP - Unbound Medicine ER -