Tamoxifen Rechallenge Decreases Metastatic Potential but Increases Cell Viability and Clonogenicity in a Tamoxifen-Mediated Cytotoxicity-Resistant Subline of Human Breast MCF7 Cancer Cells

Abstract

Background: Drug resistance is frequently found in estrogen receptor-positive (ER +) breast cancer patients during and after prolonged tamoxifen treatment. Although tamoxifen rechallenge has been proposed for treating recurrent breast tumors, the clinical benefit of this treatment is still controversial. The aims of this study are to identify the possible tamoxifen cytotoxicity-resistant subpopulation of MCF7 cells and to determine the effects of tamoxifen rechallenge on these cells. Methods: Western blot analysis was used to determine the expression levels of various epithelial-mesenchymal transition-and cell survival/proliferation-related proteins in MCF7 and MCF7-derived, tamoxifen-mediated cytotoxicity-resistant MCF7-TAM12.5 breast cancer cells. Wound healing, Transwell migration, and invasion assays were used to examine the metastatic potential of cells. Clonogenic assays, trypan blue exclusion assays, and bromodeoxyuridine assays were used to examine clonogenicity and to determine the proliferation rate of cells. Results: We found that MCF7-TAM12.5 cells exhibited higher tolerance to tamoxifenmediated cytotoxicity, higher metastatic potential, higher expression levels of XIAP, and lower expression levels of ERα/ERβ/HER2/Smac than MCF7 cells. In addition, MCF7 cells endogenously expressed Bcl-2α, whereas MCF7-TAM12.5 cells only expressed Bcl-2β. Interestingly, tamoxifen rechallenge decreased the metastatic potential but increased the proliferation and clonogenicity of MCF7-TAM12.5 cells. At the molecular level, tamoxifen rechallenge upregulated the expression of phosphorylated Aurora A and Aurora B kinase in MCF7-TAM12.5 cells.

Inflammatory Chemokines as Potential Reversal Agents for Tamoxifen Resistance in Breast Cancer Cells

“…It has been reported that tamoxifen resistant cells undergo adaptions that leads to various biological changes including loss of epithelial-like structure and acquisition of stem cells properties 20 . Here, morphological changes and E-Cad downregulation along with overexpression of cancer stem cell markers were observed in MCF-7 TamR cells compared to control cells, indicating successful establishment of tamoxifen resistance model.…”