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Translational Aspects of Erythropoietin Receptor and Hypoxia-Inducible Factors in Breast Cancer

Larsson, Anna-Maria LU (2012) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2012:7.
Abstract
The main function of erythropoietin (EPO) is in hematopoiesis where EPO stimulates increased proliferation, survival and differentiation of erythrocytic precursors in response to hypoxia. The EPO effect is mediated via binding to the EPO receptor (EPOR), which induces activation of different intracellular signaling pathways. Recombinant human EPO (rhEPO) is also used in treatment of cancer patients with anemia but some studies have reported negative effects on patient survival. Here we demonstrate a correlation between increased Hb levels and tumor response in patients with metastatic breast cancer and anemia, treated with rhEPO. The improved tumor response seen in patients with increased Hb levels might be due to improved oxygenation in... (More)
The main function of erythropoietin (EPO) is in hematopoiesis where EPO stimulates increased proliferation, survival and differentiation of erythrocytic precursors in response to hypoxia. The EPO effect is mediated via binding to the EPO receptor (EPOR), which induces activation of different intracellular signaling pathways. Recombinant human EPO (rhEPO) is also used in treatment of cancer patients with anemia but some studies have reported negative effects on patient survival. Here we demonstrate a correlation between increased Hb levels and tumor response in patients with metastatic breast cancer and anemia, treated with rhEPO. The improved tumor response seen in patients with increased Hb levels might be due to improved oxygenation in tumors counteracting negative effects of hypoxia.



EPOR has also been found in non-hematopoietic tissues and in tumors of various origins. We have evaluated EPOR expression in breast tumors from a clinical trial evaluating tamoxifen treatment versus no adjuvant treatment. We found that high EPOR expression correlates to impaired tamoxifen response in patients with estrogen receptor (ER) positive tumors. EPOR expression also correlated to survival in these patients. When further investigating EPOR function we found that EPOR knockdown impaired proliferation in ER positive, but not ER negative breast cancer cells, supposedly via modulating effects of ER activity. EPOR knockdown also improved tamoxifen response in ER positive breast cancer cells. These effects were not dependent on EPO. Our results suggest an EPO-independent but ER-dependent function of EPOR in breast cancer cells.



Hypoxia is a common feature of solid tumors and is believed to be a consequence of tumors outgrowing their vasculature. Tumor hypoxia is associated with a more aggressive phenotype and treatment resistance. The main regulators of the hypoxic response are the hypoxia-inducible factors (HIFs) 1 & 2. We have investigated HIF-1α and HIF-2α expression in breast cancer and found a correlation between HIF-2α expression and distant metastasis and impaired prognosis, suggesting that HIF-2α has an important role in tumor progression. We also show differential time and oxygen dependent regulation of the two different HIF-α subunits and differences in their contribution to inducing VEGF expression. (Less)
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author
supervisor
opponent
  • Professor Overgaard, Jens, Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Breast Cancer, Anemia, Hypoxia, Erythropoietin (EPO), EPO receptor (EPOR), Estrogen Receptor (ER), Hypoxia-Inducible Factors (HIFs), Tamoxifen Response, Proliferation
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2012:7
pages
130 pages
publisher
Center for Molecular Pathology, Faculty of Medicine
defense location
Main Lecture Hall, Department of Pathology, Skåne University Hospital, Malmö
defense date
2012-02-03 09:15
ISSN
1652-8220
ISBN
978-91-86871-69-7
language
English
LU publication?
yes
id
72dbfe2b-f39e-4e07-b11c-d6998fc9e7f0 (old id 2278410)
date added to LUP
2012-01-11 09:54:58
date last changed
2016-09-19 08:44:45
@phdthesis{72dbfe2b-f39e-4e07-b11c-d6998fc9e7f0,
  abstract     = {The main function of erythropoietin (EPO) is in hematopoiesis where EPO stimulates increased proliferation, survival and differentiation of erythrocytic precursors in response to hypoxia. The EPO effect is mediated via binding to the EPO receptor (EPOR), which induces activation of different intracellular signaling pathways. Recombinant human EPO (rhEPO) is also used in treatment of cancer patients with anemia but some studies have reported negative effects on patient survival. Here we demonstrate a correlation between increased Hb levels and tumor response in patients with metastatic breast cancer and anemia, treated with rhEPO. The improved tumor response seen in patients with increased Hb levels might be due to improved oxygenation in tumors counteracting negative effects of hypoxia. <br/><br>
<br/><br>
EPOR has also been found in non-hematopoietic tissues and in tumors of various origins. We have evaluated EPOR expression in breast tumors from a clinical trial evaluating tamoxifen treatment versus no adjuvant treatment. We found that high EPOR expression correlates to impaired tamoxifen response in patients with estrogen receptor (ER) positive tumors. EPOR expression also correlated to survival in these patients. When further investigating EPOR function we found that EPOR knockdown impaired proliferation in ER positive, but not ER negative breast cancer cells, supposedly via modulating effects of ER activity. EPOR knockdown also improved tamoxifen response in ER positive breast cancer cells. These effects were not dependent on EPO. Our results suggest an EPO-independent but ER-dependent function of EPOR in breast cancer cells.<br/><br>
<br/><br>
Hypoxia is a common feature of solid tumors and is believed to be a consequence of tumors outgrowing their vasculature. Tumor hypoxia is associated with a more aggressive phenotype and treatment resistance. The main regulators of the hypoxic response are the hypoxia-inducible factors (HIFs) 1 &amp; 2. We have investigated HIF-1α and HIF-2α expression in breast cancer and found a correlation between HIF-2α expression and distant metastasis and impaired prognosis, suggesting that HIF-2α has an important role in tumor progression. We also show differential time and oxygen dependent regulation of the two different HIF-α subunits and differences in their contribution to inducing VEGF expression.},
  author       = {Larsson, Anna-Maria},
  isbn         = {978-91-86871-69-7},
  issn         = {1652-8220},
  keyword      = {Breast Cancer,Anemia,Hypoxia,Erythropoietin (EPO),EPO receptor (EPOR),Estrogen Receptor (ER),Hypoxia-Inducible Factors (HIFs),Tamoxifen Response,Proliferation},
  language     = {eng},
  pages        = {130},
  publisher    = {Center for Molecular Pathology, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Translational Aspects of Erythropoietin Receptor and Hypoxia-Inducible Factors in Breast Cancer},
  volume       = {2012:7},
  year         = {2012},
}