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 5

EPO activates JAK/STAT signaling in breast TICs, and JAK inhibition is a potential therapeutic target in breast cancer.

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EPO activates JAK/STAT signaling in breast TICs, and JAK inhibition is a...
(A) SUM149 cells were FACS sorted into TIC (CD44+CD24–EpCAM+) and non-TIC (not CD44+CD24–EpCAM+) populations, treated with PBS or EPO (1 IU/ml) for 10 minutes, and immunoblotted with the indicated antibodies. (B) Gene-expression profiles were generated from total RNA of sorted SUM149 TICs (CD44+CD24–EpCAM+), treated with PBS or EPO (1IU/ml) for 16 hours,and subjected to ssGSEA for the indicated JAK/STAT and cancer stem cell gene signatures. (C) Mammosphere formation of CD44+CD24–EpCAM+ SUM149 cells cultured at hypoxia (2% O2) in the presence of control antibody (anti-HA) or anti-EPO antibody at the indicated dilutions. (D) Mammosphere formation of CD44+CD24–EpCAM+ SUM149 cells cultured at hypoxia (2% O2) in the presence of control antibody (anti-HA) or 2 indicated anti-EPOR antibodies (1:200). (E) 20,000 (CD44+CD24–EpCAM+) SUM149 cells were plated in duplicate in the presence of EPO (10 IU/ml) and vehicle or EPO and the JAK inhibitor TG101348 at the indicated concentrations. Spheres were counted on day 5. (F) Orthotopic MMTV-Wnt1 tumors were grown to 5 mm in length and width (average tumor volume of all groups = 60 mm3) and treated with vehicle (NT), carboplatin (Carbo), TG101348 (TG), or the combination of carboplatin and TG101348. Caliper measurements were taken weekly. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. (G) Hematocrit (HCT) measurements were done at baseline and at end point in the indicated treatment groups.