Overexpression of Insulin‐like Growth Factor Binding Protein 1 (IGFBP1) Generates Tamoxifen Resistance in Breast Cancer Cells

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Tamoxifen, a selective estrogen receptor modulator and antagonist for estrogen receptor alpha (ERα) in breast tissue, is a commonly prescribed adjuvant treatment for patients presenting with ERα‐positive breast cancer. Acquired resistance to tamoxifen remains a clinically relevant challenge for many patients receiving treatment and some patients with ERα‐positive breast cancer are innately resistant to tamoxifen treatment. The molecular mechanisms underlying both acquired and innate tamoxifen resistance are not well understood. Previous studies have shown that, in addition to ERα inhibition, tamoxifen activates the G‐protein‐coupled estrogen receptor 1 (GPER1) and activation of this receptor is associated with the development of tamoxifen resistance. GPER1 mediates the extracellular accumulation of the insulin‐like growth factor binding protein 1 (IGFBP‐1) after tamoxifen treatment resulting in the inhibition of the IGF‐1R signaling in breast cancer cells. We hypothesize sustained exposure of breast cancer cells to IGFBP‐1 will result in the development of tamoxifen resistance. Stable transfection of an IGFBP‐1 expression vector was used for sustained exposure of MCF‐7 breast cancer cells. IGF‐1R expression was decreased in MCF‐7 cells stably transfected with the IGFBP‐1 expression vector similar to IGF‐1R expression in tamoxifen resistant breast cancer cells. Similar to tamoxifen‐resistant MCF‐7 cells, the IGFBP‐1 overexpressing MCF‐7 cells also have elevated levels of activated ERK1/2. Finally, cell viability assays revealed that sustained IGFBP‐1 overexpression decreased breast cancer sensitivity to tamoxifen treatment. Taken together, these results suggest that elevated levels of IGFBP‐1 contribute to the development of tamoxifen resistance in breast cancer cells.Support or Funding InformationResearch reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103451.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.