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 3

EPO promotes progression of orthotopic C3-Tag and MMTV-Neu tumors.

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EPO promotes progression of orthotopic C3-Tag and MMTV-Neu tumors. (A) 1...
(A) 1 × 105 luciferase-expressing C3-Tag cells were implanted into the mammary fat pads of FVB/N mice. The mice were randomized to receive PBS or EPO (500 IU/kg BIW). Representative Xenogen images of mice on day 1 and day 21 after injection. (B) Living Image software (Caliper Life Sciences) was used to quantify luciferase activity of orthotopic C3-Tag tumors. Mean photons/s/cm2 is graphed with error bars representing SEM. *P ≤ 0.05 on day 21. (C) Tumor volume of orthotopically implanted NT2 cells as measured by calipers. ***P ≤ 0.001. (D and E) Kaplan-Meier curves of percentage of C3-Tag tail vein–injected mice alive in the indicated treatment groups.