Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation
Open accessAbstract
We found that the receptor for erythropoietin (EpoR) is coexpressed with human epidermal growth factor receptor-2 (HER2) in a significant percentage of human breast tumor specimens and breast cancer cell lines. Exposure of HER2 and EpoR dual-positive breast cancer cells to recombinant human erythropoietin (rHuEPO) activated cell signaling. Concurrent treatment of the cells with rHuEPO and trastuzumab reduced the cells' response to trastuzumab both in vitro and in vivo. We identified Jak2-mediated activation of Src and inactivation of PTEN as underlying mechanisms through which rHuEPO antagonizes trastuzumab-induced therapeutic effects. Furthermore, we found that compared with administration of trastuzumab alone, concurrent administration of rHuEPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer.
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In HER2-overexpressing cell lines, concurrent treatment with recombinant erythropoietin conferred trastuzumab resistance.
“In these cell lines, concurrent treatment with recombinant erythropoietin conferred trastuzumab resistance.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Liang et al., 2010
In patients with HER2+ breast cancer, concurrent administration of erythropoietin and trastuzumab correlated with a shorter progression-free and overall survival compared to patients not receiving erythropoietin.
“In patients with HER2+ breast cancer, the concurrent administration of erythropoietin and trastuzumab correlated with a shorter progression-free and overall survival compared to patients not receiving erythropoietin (Liang et al., 2010).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Liang et al., 2010
The erythropoietin receptor is co-expressed in cell lines and primary tumors that overexpress HER2.
“Most recently, the erythropoietin (Epo) receptor was found to be co-expressed in cell lines and primary tumors that overexpress HER2.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Liang et al., 2010
Src is thought to mediate resistance in part via phosphorylation and inhibition of PTEN, leading to constitutive PI3K signaling.
“Src is thought to mediate resistance in part via phosphorylation and inhibition of PTEN, leading to constitutive PI3K signaling (Liang et al., 2010).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Liang et al., 2010
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- Authors
- Liang, K., Esteva, F. J., Albarracin, C., Stemke-Hale, K., Lu, Y., Bianchini, G., Yang, C.-Y., Li, Y., Li, X., Chen, C.-T., Mills, G. B., Hortobagyi, G. N., Mendelsohn, J., Hung, M.-C., & Fan, Z.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Fan, Zhen
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 18
- Issue
- 5
- Pages
- 423-435
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3022383
- OpenAlex
- W2171518347
- Cited by
- 139
- References
- 37
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 8 · 2018: 4 · 2017: 9 · 2016: 10 · 2015: 11 · 2014: 20 · 2013: 23 · 2012: 19
- FWCI
- 9.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 016672, P50CA098258, R01CA129036, P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- recombinant human erythropoietin, trastuzumab, HER2, erythropoietin receptor, breast cancer, JAK2, Src kinase, PTEN inactivation, drug resistance, HER2-positive metastatic breast cancer, combination therapy, progression-free survival, overall survival
- MeSH terms
- Trastuzumab, Animals, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Drug Antagonism, Enzyme Activation, Erythropoietin, Female, Humans, Recombinant Proteins, Transplantation, Heterologous, Signal Transduction, Proto-Oncogene Proteins pp60(c-src), Receptors, Erythropoietin, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, PTEN Phosphohydrolase, Mice, Janus Kinase 2, Antibodies, Monoclonal, Humanized
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