title: Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal.
abstract: Erythropoietin (EPO) is a hormone that induces red blood cell production. In its recombinant form, EPO is the one of most prescribed drugs to treat anemia, including that arising in cancer patients. In randomized trials, EPO administration to cancer patients has been associated with decreased survival. Here, we investigated the impact of EPO modulation on tumorigenesis. Using genetically engineered mouse models of breast cancer, we found that EPO promoted tumorigenesis by activating JAK/STAT signaling in breast tumor-initiating cells (TICs) and promoted TIC self renewal. We determined that EPO was induced by hypoxia in breast cancer cell lines, but not in human mammary epithelial cells. Additionally, we demonstrated that high levels of endogenous EPO gene expression correlated with shortened relapse-free survival and that pharmacologic JAK2 inhibition was synergistic with chemotherapy for tumor growth inhibition in vivo. These data define an active role for endogenous EPO in breast cancer progression and breast TIC self-renewal and reveal a potential application of EPO pathway inhibition in breast cancer therapy.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhou
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Damrauer
authors.forename: Sean T
authors.initials: ST
authors.lastname: Bailey
authors.forename: Tanja
authors.initials: T
authors.lastname: Hadzic
authors.forename: Youngtae
authors.initials: Y
authors.lastname: Jeong
authors.forename: Kelly
authors.initials: K
authors.lastname: Clark
authors.forename: Cheng
authors.initials: C
authors.lastname: Fan
authors.forename: Laura
authors.initials: L
authors.lastname: Murphy
authors.forename: Cleo Y
authors.initials: CY
authors.lastname: Lee
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: David
authors.initials: D
authors.lastname: Darr
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Maximilian
authors.initials: M
authors.lastname: Diehn
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy; D063646:Carcinogenesis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D018450:Disease Progression; D018572:Disease-Free Survival; D042783:Endothelial Cells / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
chemical_list: D013778:Tetrazolium Salts; D013844:Thiazoles; D004921:Erythropoietin; C022616:thiazolyl blue