Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 1/2019

Open Access 01-12-2019 | Erythropoietin | Research article

Serum erythropoietin levels, breast cancer and breast cancer-initiating cells

Authors: Kruttika Bhat, Kiri Sandler, Sara Duhachek-Muggy, Claudia Alli, Fei Cheng, Neda A. Moatamed, Clara E. Magyar, Lin Du, Gang Li, Susan McCloskey, Erina Vlashi, Frank Pajonk

Published in: Breast Cancer Research | Issue 1/2019

Login to get access

Abstract

Background

Cancer is frequently associated with tumor-related anemia, and many chemotherapeutic agents impair hematopoiesis, leading to impaired quality of life for affected patients. The use of erythropoiesis-stimulating agents has come under scrutiny after prospective clinical trials using recombinant erythropoietin to correct anemia reported increased incidence of thromboembolic events and cancer-related deaths. Furthermore, previous preclinical reports indicated expansion of the pool of breast cancer-initiating cells when erythropoietin was combined with ionizing radiation.

Methods

Using four established breast cancer cell lines, we test the effects of recombinant human erythropoietin and the number of breast cancer-initiating cells in vitro and in vivo and study if recombinant human erythropoietin promotes the phenotype conversion of non-tumorigenic breast cancer cells into breast cancer-initiating cells. In a prospective study, we evaluate whether elevated endogenous serum erythropoietin levels correlate with increased numbers of tumor-initiating cells in a cohort of breast cancer patients who were scheduled to undergo radiation treatment.

Results

Our results indicate that recombinant erythropoietin increased the number of tumor-initiating cells in established breast cancer lines in vitro. Irradiation of breast cancer xenografts caused a phenotype conversion of non-stem breast cancer cells into induced breast cancer-initiating cells. This effect coincided with re-expression of the pluripotency factors c-Myc, Sox2, and Oct4 and was enhanced by recombinant erythropoietin. Hemoglobin levels were inversely correlated with serum erythropoietin levels, and the latter were correlated with disease stage. However, tumor sections revealed a negative correlation between serum erythropoietin levels and the number of ALDH1A3-positive cells, a marker for breast cancer-initiating cells.

Conclusions

We conclude that physiologically slow-rising serum erythropoietin levels in response to tumor-related or chemotherapy-induced anemia, as opposed to large doses of recombinant erythropoietin, do not increase the pool of breast cancer-initiating cells.
Appendix
Available only for authorised users
Literature
1.
Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366(9503):2087–106.PubMedCrossRef
2.
Henke M, Sindlinger F, Ikenberg H, Gerds T, Schumacher M. Blood hemoglobin level and treatment outcome of early breast cancer. Strahlenther Onkol. 2004;180(1):45–51.PubMedCrossRef
3.
Gaspar BL, Sharma P, Das R. Anemia in malignancies: pathogenetic and diagnostic considerations. Hematology. 2015;20(1):18–25.PubMedCrossRef
4.
Lacombe C, Mayeux P. Biology of erythropoietin. Haematologica. 1998;83(8):724–32.PubMed
5.
Phillips TM, Kim K, Vlashi E, McBride WH, Pajonk F. Effects of recombinant erythropoietin on breast cancer-initiating cells. Neoplasia. 2007;9(12):1122–9.PubMedPubMedCentralCrossRef
6.
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672–9.PubMedCrossRef
7.
Cao Y, Lathia JD, Eyler CE, Wu Q, Li Z, Wang H, et al. Erythropoietin receptor signaling through STAT3 is required for glioma stem cell maintenance. Genes Cancer. 2010;1(1):50–61.PubMedPubMedCentralCrossRef
8.
Eccles TG, Patel A, Verma A, Nicholson D, Lukes Y, Tuttle RM, et al. Erythropoietin and the erythropoietin receptor are expressed by papillary thyroid carcinoma from children and adolescents. Expression of erythropoietin receptor might be a favorable prognostic indicator. Ann Clin Lab Sci. 2003;33(4):411–22.PubMed
9.
Arcasoy MO, Amin K, Vollmer RT, Jiang X, Demark-Wahnefried W, Haroon ZA. Erythropoietin and erythropoietin receptor expression in human prostate cancer. Mod Pathol. 2005;18(3):421–30.PubMedCrossRef
10.
Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373(9674):1532–42.PubMedCrossRef
11.
Henke M, Laszig R, Rübe C, Schäfer U, Haase KD, Schilcher B, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;262:1255–60.CrossRef
12.
Leyland-Jones B. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol. 2003;4(8):459–60.PubMedCrossRef
13.
Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007:JCO. 2006;07:1514.
14.
Vlashi E, Kim K, Lagadec C, Donna LD, McDonald JT, Eghbali M, et al. In vivo imaging, tracking, and targeting of cancer stem cells. J Natl Cancer Inst. 2009;101(5):350–9.PubMedPubMedCentralCrossRef
15.
Hu Y, Smyth GK. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009;347(1–2):70–8.PubMed
16.
Lagadec C, Vlashi E, Frohnen P, Alhiyari Y, Chan M, Pajonk F. The RNA-binding protein Musashi-1 regulates proteasome subunit expression in breast cancer- and glioma-initiating cells. Stem Cells. 2014;32(1):135–44.PubMedPubMedCentralCrossRef
17.
Xu H, Fu J, Ha SW, Ju D, Zheng J, Li L, et al. The CCAAT box-binding transcription factor NF-Y regulates basal expression of human proteasome genes. Biochim Biophys Acta. 2012;1823(4):818–25.PubMedCrossRef
18.
Vlashi E, Lagadec C, Chan M, Frohnen P, McDonald AJ, Pajonk F. Targeted elimination of breast cancer cells with low proteasome activity is sufficient for tumor regression. Breast Cancer Res Treat. 2013;141(2):197–203.PubMedCrossRef
19.
20.
21.
Phillips T, Mcbride W, Pajonk F. The response of CD24(−/low)/CD44(+) breast cancer-initiating cells to radiation. J Natl Cancer Inst. 2006;98(24):1777–85.PubMedCrossRef
22.
Lagadec C, Vlashi E, Della Donna L, Meng Y, Dekmezian C, Kim K, et al. Survival and self-renewing capacity of breast cancer initiating cells during fractionated radiation treatment. Breast Cancer Res. 2010;12(1):R13.PubMedPubMedCentralCrossRef
23.
Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM. WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci U S A. 2007;104(2):618–23.PubMedPubMedCentralCrossRef
24.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.PubMedPubMedCentralCrossRef
25.
Myklebust JH, Blomhoff HK, Rusten LS, Stokke T, Smeland EB. Activation of phosphatidylinositol 3-kinase is important for erythropoietin-induced erythropoiesis from CD34(+) hematopoietic progenitor cells. Exp Hematol. 2002;30(9):990–1000.PubMedCrossRef
26.
Charafe-Jauffret E, Ginestier C, Iovino F, Tarpin C, Diebel M, Esterni B, et al. Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer. 2010;16(1):45–55.CrossRef
27.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555–67.PubMedPubMedCentralCrossRef
28.
Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 2009;69(8):3382–9.PubMedPubMedCentralCrossRef
29.
Resetkova E, Reis-Filho JS, Jain RK, Mehta R, Thorat MA, Nakshatri H, et al. Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment. Breast Cancer Res Treat. 2010;123(1):97–108.PubMedCrossRef
30.
Vlashi E, Lagadec C, Vergnes L, Matsutani T, Masui K, Poulou M, et al. Metabolic state of glioma stem cells and nontumorigenic cells. Proc Natl Acad Sci U S A. 2011;108(38):16062–7.PubMedPubMedCentralCrossRef
31.
Lagadec C, Vlashi E, Bhuta S, Lai C, Mischel P, Werner M, et al. Tumor cells with low proteasome subunit expression predict overall survival in head and neck cancer patients. BMC Cancer. 2014;14(1):152.PubMedPubMedCentralCrossRef
32.
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.PubMedCrossRef
33.
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63(18):5821–8.PubMed
34.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.PubMedCrossRef
35.
Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A. 2003;100(25):15178–83.PubMedPubMedCentralCrossRef
36.
Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 2005;65(20):9328–37.PubMedCrossRef
37.
Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65(23):10946–51.PubMedCrossRef
38.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.PubMedCrossRef
39.
Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104(24):10158–63.PubMedPubMedCentralCrossRef
40.
Prince ME. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104:973–8.PubMedPubMedCentralCrossRef
41.
Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030–7.PubMedCrossRef
42.
Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2007;15(3):504–14.PubMedCrossRef
43.
Marcato P, Dean CA, Pan D, Araslanova R, Gillis M, Joshi M, et al. Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells. 2011;29(1):32–45.PubMedCrossRef
44.
Henke M, Guttenberger R, Barke A, Pajonk F, Potter R, Frommhold H. Erythropoietin for patients undergoing radiotherapy: a pilot study. Radiother Oncol. 1999;50(2):185–90.PubMedCrossRef
45.
Overgaard J, Hoff CM, Hansen HS, Specht L, Overgaard M, Lassen P, et al. DAHANCA 10 - effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group. Radiother Oncol. 2018;127(1):12–9.PubMedCrossRef
46.
Westphal G, Niederberger E, Blum C, Wollman Y, Knoch TA, Rebel W, et al. Erythropoietin and G-CSF receptors in human tumor cells: expression and aspects regarding functionality. Tumori. 2002;88(2):150–9.PubMedCrossRef
47.
Thews O, Koenig R, Kelleher DK, Kutzner J, Vaupel P. Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br J Cancer. 1998;78(6):752–6.PubMedPubMedCentralCrossRef
48.
Silver DF, Piver MS. Effects of recombinant human erythropoietin on the antitumor effect of cisplatin in SCID mice bearing human ovarian cancer: a possible oxygen effect. Gynecol Oncol. 1999;73(2):280–4.PubMedCrossRef
49.
Stuben G, Thews O, Pottgen C, Knuhmann K, Vaupel P, Stuschke M. Recombinant human erythropoietin increases the radiosensitivity of xenografted human tumours in anaemic nude mice. J Cancer Res Clin Oncol. 2001;127(6):346–50.PubMedCrossRef
50.
Westenfelder C, Baranowski RL. Erythropoietin stimulates proliferation of human renal carcinoma cells. Kidney Int. 2000;58(2):647–57.PubMedCrossRef
51.
Acs G, Acs P, Beckwith SM, Pitts RL, Clements E, Wong K, et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res. 2001;61(9):3561–5.PubMed
52.
Yasuda Y, Fujita Y, Musha T, Tanaka H, Shiokawa S, Nakamatsu K, et al. Expression of erythropoietin in human female reproductive organs. Ital J Anat Embryol. 2001;106(2 Suppl 2):215–22.PubMed
53.
Yasuda Y, Musha T, Tanaka H, Fujita Y, Fujita H, Utsumi H, et al. Inhibition of erythropoietin signalling destroys xenografts of ovarian and uterine cancers in nude mice. Br J Cancer. 2001;84(6):836–43.PubMedPubMedCentralCrossRef
54.
Yasuda Y, Fujita Y, Matsuo T, Koinuma S, Hara S, Tazaki A, et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis. 2003;24(6):1021–9.PubMedCrossRef
55.
Belenkov AI, Shenouda G, Rizhevskaya E, Cournoyer D, Belzile JP, Souhami L, et al. Erythropoietin induces cancer cell resistance to ionizing radiation and to cisplatin. Mol Cancer Ther. 2004;3(12):1525–32.PubMed
56.
Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458(7239):780-3.
57.
Bao S. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.PubMedCrossRef
58.
Zhou B, Damrauer JS, Bailey ST, Hadzic T, Jeong Y, Clark K, et al. Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal. J Clin Invest. 2014;124(2):553–63.PubMedPubMedCentralCrossRef
59.
Reichel C. The overlooked difference between human endogenous and recombinant erythropoietins and its implication for sports drug testing and pharmaceutical drug design. Drug Test Anal. 2011;3(11–12):883–91.PubMedCrossRef
Metadata
Title
Serum erythropoietin levels, breast cancer and breast cancer-initiating cells
Authors
Kruttika Bhat
Kiri Sandler
Sara Duhachek-Muggy
Claudia Alli
Fei Cheng
Neda A. Moatamed
Clara E. Magyar
Lin Du
Gang Li
Susan McCloskey
Erina Vlashi
Frank Pajonk
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2019
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-019-1100-9

Other articles of this Issue 1/2019

Breast Cancer Research 1/2019 Go to the issue

Research article

Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers

Research article

Prediction and clinical utility of a contralateral breast cancer risk model

Research article

Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer

Research article

Automated volumetric breast density measures: differential change between breasts in women with and without breast cancer

Review

Neutrophil extracellular traps in breast cancer and beyond: current perspectives on NET stimuli, thrombosis and metastasis, and clinical utility for diagnosis and treatment

Research article

Nintedanib plus letrozole in early breast cancer: a phase 0/I pharmacodynamic, pharmacokinetic, and safety clinical trial of combined FGFR1 and aromatase inhibition
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits