Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal
Bing Zhou, Jeffrey S. Damrauer, Sean T. Bailey, Tanja Hadzic, Youngtae Jeong, Kelly Clark, Cheng Fan, Laura Murphy, Cleo Y. Lee, Melissa A. Troester, C. Ryan Miller, Jian Jin, David Darr, Charles M. Perou, Ross L. Levine, Maximilian Diehn, William Y. Kim
Bing Zhou, Jeffrey S. Damrauer, Sean T. Bailey, Tanja Hadzic, Youngtae Jeong, Kelly Clark, Cheng Fan, Laura Murphy, Cleo Y. Lee, Melissa A. Troester, C. Ryan Miller, Jian Jin, David Darr, Charles M. Perou, Ross L. Levine, Maximilian Diehn, William Y. Kim
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Research Article Oncology

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

Bing Zhou, Jeffrey S. Damrauer, Sean T. Bailey, Tanja Hadzic, Youngtae Jeong, Kelly Clark, Cheng Fan, Laura Murphy, Cleo Y. Lee, Melissa A. Troester, C. Ryan Miller, Jian Jin, David Darr, Charles M. Perou, Ross L. Levine, Maximilian Diehn, William Y. Kim

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Figure 6

Endogenous EPO expression correlates negatively with relapse-free survival and is produced by breast cancer cell lines and tumor endothelial cells.

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Endogenous EPO expression correlates negatively with relapse-free surviv...
(A) Breast tumors (337 patients [GSE18229] and 855 patients [GSE26338] were rank ordered based on their EPO expression and divided into those with high and low EPO expression (high: top 2 tertiles, low: bottom tertile). P = 0.0088 for UNC337, P = 0.0012 for GSE26338, log rank test. (B) EPO mRNA levels from HMECs and the indicated breast cancer cell lines cultured in 21% and 1% O2 using TaqMan quantitative RT-PCR. (C) EPO protein as measured by ELISA on conditioned medium from the indicated cell lines after culture under 21% O2 or 1% O2 for 16 hours. (D) Microarray gene expression for EPO was abstracted from a publically available data set (GSE7413) in which breast cancer–associated endothelial cells or endothelial cells from adjacent normal were laser capture microdissected. Relative gene expression Cy5 (tumor)/Cy3(reference) is shown. (E) EPO mRNA levels from HUVECs cultured in 21% and 1% O2 were measured by TaqMan quantitative PCR. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.