Recombinant human erythropoietin alters gene expression and stimulates proliferation of MCF-7 breast cancer cells

Trošt, Nina; Stepišnik, Tina; Berne, Sabina; Pucer, Anja; Petan, Toni; Komel, Radovan; Debeljak, Nataša

doi:10.2478/raon-2013-0056

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…EPO can stimulate the growth of EPO-R-positive tumor cells and thereby enhance patient tumorigenesis (30,31). In response to chimeric activator exposure, we compared proliferation of EPO-R-positive MCF-7 and BT-549 cells with EPO-R-negative HeLa cells (30,31). MCF-7 and BT-549 cell lines responded to 10F7-EPO (logEC 50 = −6.7 M) but not 10F7-EPO R150A ; HeLa cells did not significantly respond to either protein.…”

Section: Resultsmentioning

confidence: 99%

Targeted erythropoietin selectively stimulates red blood cell expansion in vivo

Burrill

Vernet

Collins

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The design of cell-targeted protein therapeutics can be informed by natural protein-protein interactions that use cooperative physical contacts to achieve cell type specificity. Here we applied this approach in vivo to the anemia drug erythropoietin (EPO), to direct its activity to EPO receptors (EPO-Rs) on red blood cell (RBC) precursors and prevent interaction with EPO-Rs on nonerythroid cells, such as platelets. Our engineered EPO molecule was mutated to weaken its affinity for EPO-R, but its avidity for RBC precursors was rescued via tethering to an antibody fragment that specifically binds the human RBC marker glycophorin A (huGYPA). We systematically tested the impact of these engineering steps on in vivo markers of efficacy, side effects, and pharmacokinetics. huGYPA transgenic mice dosed with targeted EPO exhibited elevated RBC levels, with only minimal platelet effects. This in vivo selectivity depended on the weakening EPO mutation, fusion to the RBC-specific antibody, and expression of huGYPA. The terminal plasma half-life of targeted EPO was ∼28.3 h in transgenic mice vs. ∼15.5 h in nontransgenic mice, indicating that huGYPA on mature RBCs acted as a significant drug sink but did not inhibit efficacy. In a therapeutic context, our targeting approach may allow higher restorative doses of EPO without platelet-mediated side effects, and also may improve drug pharmacokinetics. These results demonstrate how rational drug design can improve in vivo specificity, with potential application to diverse protein therapeutics.protein engineering | drug targeting | platelet | scFv

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Section: Resultsmentioning

confidence: 99%

Targeted erythropoietin selectively stimulates red blood cell expansion in vivo

Burrill

Vernet

Collins

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Concern has been identified that erythropoiesis-simulating agents are associated with decreased tumor progression and survival. (44–46) In this context, some centers are exploring the effects of agents such as romiplostim (a thrombopoietin receptor agonist) to maintain platelets >100 × 10 9 /L in patients being treated with cytotoxic chemotherapy. Limited data report a 15% DVT rate and are not adequate to consider impact on progression and/or survival.…”

Section: Discussionmentioning

confidence: 99%

Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer

Bottsford-Miller

Choi

Dalton

et al. 2015

Clinical Cancer Research

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Purpose We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy. Experimental Design The medical records of patients with recurrent or progressive ovarian cancer were retrospectively queried for changes in platelet and CA-125 levels during primary therapy. In vitro co-culture experiments and in vivo orthotopic models of human ovarian cancer in mice were used to test the effect of modulating platelet levels on tumor growth and responsiveness to docetaxel. Results Thrombocytosis at the diagnosis of ovarian cancer correlated with decreased interval to progression (p = 0.05) and median overall survival (p = 0.007). Mean platelet levels corrected during primary therapy and rose at recurrence. Contrary to treatment-responsive patients, in a cohort of patients refractory to primary therapy, platelet levels did not normalize during therapy. In A2780, HeyA8, and SKOV3-ip1 ovarian cancer cell lines, platelet co-culture protected against apoptosis (p < 0.05). In orthotopic models of human ovarian cancer, platelet depletion resulted in 70% reduced mean tumor weight (p < 0.05). Compared to mice treated with docetaxel, mice treated with both docetaxel and platelet-depleting antibody had a 62% decrease in mean tumor weight (p = 0.04). Platelet transfusion increased mean aggregate tumor weight 2.4-fold (p < 0.05), blocked the effect of docetaxel on tumor growth (p = 0.55) and decreased tumor cell apoptosis. Pre-transfusion aspirinization of the platelets blocked the growth-promoting effects of transfusion. Conclusions Platelet-driven effects of chemotherapy response may explain clinical observations.

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“…In recent years functional autocrine/paracrine EPO/EPO-R systems have been described in human cancer cells originating from breast cancer, cervical cancer, melanoma and prostate cancer. These data suggest that the EPO/EPO-R axis may affect tumor growth, progression and metastasis [30][31][32][33][34][35].…”

Section: Discussionmentioning

confidence: 81%

Clinicopathological factors associated with novel prognostic markers for patients with triple negative breast cancer

Badowska-Kozakiewicz¹,

Budzik²,

Liszcz³

et al. 2019

aoms

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Introduction: Triple negative breast cancer (TNBC) is characterized by a worse prognosis than other breast cancer subtypes. TNBC is defined by lack of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. The aim of this analysis was to evaluate the relationship between immunohistochemical expression of novel prognostic markers (erythropoietin (EPO) and erythropoietin receptor (EPO-R)) and clinicopathological features of TNBC and non-TNBC patients. Material and methods: Our analysis was conducted on a group of 162 patients with breast carcinoma with lymph node metastasis (111 TNBC and 51 non-TNBC). All statistical analyses were performed with SPSS software v 12.0. Results: Histopathologic subtyping of the 111 triple negative breast cancers identified 89.1% invasive ductal carcinomas of no special type and 10.9% other special types of cancers. TNBC more often presented EPO-R and EPO expression (36%; 37.8%) than non-TNBC (23.5%; 29.4%). Non-TNBC subgroup showed statistically significant correlation only between Ki-67 expression and histological grade (G1-G3) (p < 0.001), while TNBC subgroup demonstrated significant correlation between Ki-67 expression and histological grade (G1-G3) and tumor size (pT1-pT4) as well (p = 0.002; p = 0.042), between the EPO-R expression and histological grade (G1-G3) (p < 0.001). Conclusions: The relationship between the expression of EPO-R and histological malignancy grade in triple negative breast cancer, suggests that the present EPO-R expression in TNBC may constitute an additional prognostic factor.

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Recombinant human erythropoietin alters gene expression and stimulates proliferation of MCF-7 breast cancer cells

Cited by 7 publications

References 29 publications

Targeted erythropoietin selectively stimulates red blood cell expansion in vivo

Targeted erythropoietin selectively stimulates red blood cell expansion in vivo

Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer

Clinicopathological factors associated with novel prognostic markers for patients with triple negative breast cancer

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