A functional drug re-purposing screening identifies carfilzomib as a drug preventing 17 beta-estradiol: ER alpha signaling and cell proliferation in breast cancer cells

摘要

Most cases of breast cancer (BC) are estrogen receptor cc-positive (ER alpha+) at diagnosis. The presence of ER alpha drives the therapeutic approach for this disease, which often consists of endocrine therapy (ET). 4OH-Tamoxifen and faslodex (i.e., fulvestrant- ICI182,780) are two ETs that render tumor cells insensitive to 17 beta-estradiol (E2)-dependent proliferative stimuli and prevent BC progression. However, ET has limitations and serious failures in different tissues and organs. Thus, there is an urgent need to identify novel drugs to fight BC in the clinic. Re-positioning of old drugs for new clinical purposes is an attractive alternative for drug discovery. For this analysis, we focused on the modulation of intracellular ER alpha levels in BC cells as target for the screening of about 900 Food and Drug Administration (FDA) approved compounds that would hinder E2:ER alpha signaling and inhibit BC cell proliferation. We found that carfilzomib induces ER alpha degradation and prevents E2 signaling and cell proliferation in two ER alpha+ BC cell lines. Remarkably, the analysis of carfilzomib effects on a cell model system with an acquired resistance to 4OH-tamoxifen revealed that this drug has an antiproliferative effect superior to faslodex in BC cells. Therefore, our results identify carfilzomib as a drug preventing E2:ER alpha signaling and cell proliferation in BC cells and suggest its possible re-position for the treatment of ER alpha+ BC as well as for those diseases that have acquired resistance to 4OH-tamoxifen. (C) 2017 Elsevier B.V. All rights reserved.