This study explores if radiation and erythropoietin (Epo) synergize to alter the self-renewal of breast cancer stem cells (BCSCs) and to reprogram differentiated breast cancer (BC) cells into induced breast cancer stem cells (iBCSCs). Using established cell lines and a unique imaging system for breast cancer stem cells, patient-derived tumor samples and clinical pretreatment blood samples of BC patients undergoing radiation treatment (RT) it will explore if Epo acts on irradiated BCSCs directly, if it alters the BCSC nich, and which pathways are engaged during radiation-induced reprogramming of differentiated BC cells in the presence of Epo. In a prospective clinical study we will test, if high serum Epo level correlate with high BCSC burden, nodal status and local control after breast-conserving surgery (BCS) and RT. We hypothesize, that ionizing radiation reprograms differentiated breast cancer cells into radioresistant iBCSCs and that endogenous Epo synergizes with radiation to increase the BCSCs pool, thereby impairing radiation therapy outcome. Limited stage BC is usually treated with mastectomy or BCS and RT. For RT, low hemoglobin (Hb) levels predict early treatment failure. Attempts to increase Hb levels using Epo led to inferior outcome of BC patients, suggesting that signaling through the Epo receptor promotes tumor growth. Recent studies indicate that BCs are organized hierarchically with a small population of BCSCs, capable of re-growing a tumor while their progeny lack this feature. According to the cancer stem cell (CSC) hypothesis, cure is only possible if all CSCs are eliminated, suggesting that the deleterious effects of Epo were mediated by effects of Epo on BCSCs. Because of the rare nature of BCSCs, the effects of Epo on these cells have not been investigated. BCSCs are relatively radioresistant. Furthermore, EpoR expression on tumor cells is inversely correlated with prognosis and rhEpo and RT increases the number of BCSCs in vitro possibly through RT-induced reprogramming of differentiated BC cells into iBCSCs. The hypothesis will be tested by 1) investigating the effects of Epo and RT on BCSCs, 2) exploring the pathways activated during reprogramming, and 3) testing if endogenous Epo affects BCSCs clinically. Cancer-related anemia is a condition with a high incidence in cancer patients. This proposal will study if erythropoietin activates pathways that synergize with radiation to increase the pool of therapy-resistant BCSCs and evaluate if endogenous Epo level correlate with BCSC burden and clinical outcome. The long-term goals of this proposal are to study under which circumstances Epo interferes with BCSC numbers and treatment outcome. Understanding the pathways may lead to novel combined treatments that will improve BC treatment outcome.

Public Health Relevance

This proposal will study the effects of erythropoietin at RT on cancer stem cells in experimental models and clinical patient samples. It aims to understand how erythropoietin affects cancer stem cells to uncover novel ways to improve the efficacy of radiation treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Ahmed, Mansoor M
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Duhachek-Muggy, Sara; Bhat, Kruttika; Vlashi, Erina et al. (2017) Growth Differentiation Factor 11 does not Mitigate the Lethal Effects of Total-Abdominal Irradiation. Radiat Res 188:469-475
Qi, Xiangrong Sharon; Pajonk, Frank; McCloskey, Susan et al. (2017) Radioresistance of the breast tumor is highly correlated to its level of cancer stem cell and its clinical implication for breast irradiation. Radiother Oncol 124:455-461
Vlashi, Erina; Chen, Allen M; Boyrie, Sabrina et al. (2016) Radiation-Induced Dedifferentiation of Head and Neck Cancer Cells Into Cancer Stem Cells Depends on Human Papillomavirus Status. Int J Radiat Oncol Biol Phys 94:1198-206
Vlashi, Erina; Pajonk, Frank (2015) The metabolic state of cancer stem cells-a valid target for cancer therapy? Free Radic Biol Med 79:264-8
Vlashi, Erina; Pajonk, Frank (2015) Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol 31:28-35
Yu, Victoria Y; Nguyen, Dan; Pajonk, Frank et al. (2015) Incorporating cancer stem cells in radiation therapy treatment response modeling and the implication in glioblastoma multiforme treatment resistance. Int J Radiat Oncol Biol Phys 91:866-75
Lagadec, Chann; Vlashi, Erina; Bhuta, Sunita et al. (2014) Tumor cells with low proteasome subunit expression predict overall survival in head and neck cancer patients. BMC Cancer 14:152
Vlashi, Erina; Lagadec, Chann; Vergnes, Laurent et al. (2014) Metabolic differences in breast cancer stem cells and differentiated progeny. Breast Cancer Res Treat 146:525-34
Lagadec, Chann; Vlashi, Erina; Frohnen, Patricia et al. (2014) The RNA-binding protein Musashi-1 regulates proteasome subunit expression in breast cancer- and glioma-initiating cells. Stem Cells 32:135-44
Vlashi, Erina; Lagadec, Chann; Chan, Mabel et al. (2013) Targeted elimination of breast cancer cells with low proteasome activity is sufficient for tumor regression. Breast Cancer Res Treat 141:197-203

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