TY - JOUR
T1 - Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-Mediated Src activation and PTEN inactivation
AU - Liang, Ke
AU - Esteva, Francisco J.
AU - Albarracin, Constance
AU - Stemke-Hale, Katherine
AU - Lu, Yang
AU - Bianchini, Giampaolo
AU - Yang, Ching Yi
AU - Li, Yong
AU - Li, Xinqun
AU - Chen, Chun Te
AU - Mills, Gordon B.
AU - Hortobagyi, Gabriel N.
AU - Mendelsohn, John
AU - Hung, Mien Chie
AU - Fan, Zhen
N1 - Funding Information:
This work was supported by a National Institutes of Health (NIH) R01 award (CA129036 to Z.F.), by research awards from the Breast Cancer Research Foundation (to F.J.E., G.B.M., G.N.H., J.M., M.-C.H., and Z.F.), and by the Cancer Center Support Grant CA016672 from the National Cancer Institute. We thank Drs. Wenya Xia and Xiaoming Xie for technical support with immunohistochemical staining and the animal experiments, Stephanie Deming for editorial assistance, and the staff of the Breast Cancer Management System, Department of Breast Medical Oncology, MD Anderson Cancer Center, for management of the patient data used in the current study.
PY - 2010/11/16
Y1 - 2010/11/16
N2 - We found that the receptor for erythropoietin (EpoR) is coexpressed with human epidermal growth factor receptor-2 (HER2) in a significant percentage of human breast tumor specimens and breast cancer cell lines. Exposure of HER2 and EpoR dual-positive breast cancer cells to recombinant human erythropoietin (rHuEPO) activated cell signaling. Concurrent treatment of the cells with rHuEPO and trastuzumab reduced the cells' response to trastuzumab both in vitro and in vivo. We identified Jak2-mediated activation of Src and inactivation of PTEN as underlying mechanisms through which rHuEPO antagonizes trastuzumab-induced therapeutic effects. Furthermore, we found that compared with administration of trastuzumab alone, concurrent administration of rHuEPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer.
AB - We found that the receptor for erythropoietin (EpoR) is coexpressed with human epidermal growth factor receptor-2 (HER2) in a significant percentage of human breast tumor specimens and breast cancer cell lines. Exposure of HER2 and EpoR dual-positive breast cancer cells to recombinant human erythropoietin (rHuEPO) activated cell signaling. Concurrent treatment of the cells with rHuEPO and trastuzumab reduced the cells' response to trastuzumab both in vitro and in vivo. We identified Jak2-mediated activation of Src and inactivation of PTEN as underlying mechanisms through which rHuEPO antagonizes trastuzumab-induced therapeutic effects. Furthermore, we found that compared with administration of trastuzumab alone, concurrent administration of rHuEPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=78249236544&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78249236544&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2010.10.025
DO - 10.1016/j.ccr.2010.10.025
M3 - Article
C2 - 21075308
AN - SCOPUS:78249236544
VL - 18
SP - 423
EP - 435
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 5
ER -