title: Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation.
abstract: 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.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
authors.forename: Ke
authors.initials: K
authors.lastname: Liang
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.forename: Constance
authors.initials: C
authors.lastname: Albarracin
authors.forename: Katherine
authors.initials: K
authors.lastname: Stemke-Hale
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Bianchini
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Xinqun
authors.initials: X
authors.lastname: Li
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Chen
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: John
authors.initials: J
authors.lastname: Mendelsohn
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004336:Drug Antagonism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000502:physiology*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004921:Erythropoietin; D053614:Janus Kinase 2; D051059:PTEN Phosphohydrolase; D016392:Proto-Oncogene Proteins pp60(c-src); D018719:Erb-b2 Receptor Tyrosine Kinases; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C507924:JAK2 protein, human; C494929:PTEN protein, human