Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal
Bing Zhou, … , Maximilian Diehn, William Y. Kim
Bing Zhou, … , Maximilian Diehn, William Y. Kim
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(2):553-563. https://doi.org/10.1172/JCI69804.
View: Text | PDF
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

×

Figure 2

EPO decreases the percentage of breast cancer GEMMs living over time yet does not affect breast cancer GEMM cell lines in vitro.

Options: View larger image (or click on image) Download as PowerPoint
EPO decreases the percentage of breast cancer GEMMs living over time yet...
(A) Kaplan-Meier survival curves of MMTV-Neu and C3-Tag mice randomized to saline or EPO (500 IU/kg BIW) injections. (MMTV-Neu: P = 0.05, C3-Tag: P = 0.04). Tumors were sectioned and H&E stained. (B) Indicated cell lines were cultured in the presence of increasing concentrations of EPO (1, 5, and 10 IU/ml, replenished to the culture every other day). and proliferation was detected by MTT assay. (C) Cell lines were cultured in the presence of PBS or EPO (1 IU/ml) for 16 hours and EdU for 1 hour. They were then analyzed for EdU incorporation by flow cytometry. (D) Indicated cell lines were treated with vehicle, etoposide (50 μM), or etoposide (50 μM) and EPO (10 IU/ml) for 24 hours. Whole cell extracts were western blotted with the indicated antibodies. (E) Indicated cell lines were treated with DMSO, etoposide (50 μM), or etoposide (50 μM) and EPO (10 IU/ml) for 24 hours. Percentage of apoptotic cells was then determined by flow analysis using Alexa Fluor 488 annexin V/PI Cell Apoptosis Kit (Invitrogen). ***P ≤ 0.001.