Overexpression of the erythropoietin receptor in RAMA 37 breast cancer cells alters cell growth and sensitivity to tamoxifen

Ilkovičová,Lenka; Trošt,Nina; Szentpéteriová,Erika; Solár,Peter; Komel,Radovan; Debeljak,Nataša

doi:10.3892/ijo.2017.4061

Overexpression of the erythropoietin receptor in RAMA 37 breast cancer cells alters cell growth and sensitivity to tamoxifen

Authors:
- Lenka Ilkovičová
- Nina Trošt
- Erika Szentpéteriová
- Peter Solár
- Radovan Komel
- Nataša Debeljak
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Affiliations: Department of Cell Biology, Institute of Biology and Ecology, Faculty of Science, P.J. Šafárik University in Košice, 040 01 Košice, Slovakia, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka 565-0871, Japan, Medical Centre for Molecular Biology, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
Published online on: June 28, 2017 https://doi.org/10.3892/ijo.2017.4061
Pages: 737-746

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Abstract

Erythropoietin (EPO) is the main regulator of erythropoiesis, and its receptor (EPOR) is expressed in various tissues, including tumors. Expression of EPOR in breast cancer tissue has been shown to correlate with expression of the estrogen receptor (ER). However, EPOR promotes proliferation in an EPO-independent manner. In patients with breast cancer, EPOR is associated with impaired tamoxifen response in ER-positive tumors, but not in ER-negative tumors. Furthermore, a positive correlation between EPOR/ER status and increased local cancer recurrence has been demonstrated, and EPOR expression is associated with G-protein coupled ER (GPER). Herein, we assessed the effects of EPOR on cell physiology and tamoxifen response in the absence of EPO stimulation using two cell lines that differ only in their EPOR expression status: RAMA 37 cells (low EPOR expression) and RAMA 37-28 cells (high EPOR expression). Alterations in cell growth, morphology, response to tamoxifen cytotoxicity, and EPOR-activated signal transduction were observed. RAMA 37 cells showed higher proliferation capacity without tamoxifen treatment, while RAMA 37-28 cells were more resistant to tamoxifen and proliferated more rapidly in the presence of tamoxifen. EPOR overexpression induced cell-morphology changes upon tamoxifen treatment, which resulted in the production of cell protrusions and subsequent cell death. Short-term treatment with tamoxifen (6 h) prompted RAMA 37 cells to acquired longer protrusions than RAMA 37-28 cells, which indicated a pre-apoptotic stage. Furthermore, prolonged treatment with tamoxifen (72 h) caused a greater reduction in RAMA 37 cell numbers, which indicated a higher rate of cell death. RAMA 37-28 cells showed prolonged activation of AKT signaling. We propose sustained AKT phosphorylation in EPOR-overexpressing cells as a mechanism that can lead to EPOR-induced tamoxifen resistance.

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