In silico screening for ERα downmodulators identifies thioridazine as an anti-proliferative agent in primary, 4OH-tamoxifen-resistant and Y537S ERα-expressing breast cancer cells

Abstract

PurposeMost breast cancers (BCs) express estrogen receptor (ER) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (i.e., ICI182,780-ICI). Unfortunately, a high fraction of ET-treated women relapses and become resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using the modulation of the ER intracellular content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ER content in BC cells.\n\nMethodsWe screened in silico more than 60,000 compounds to identify FDA-approved drugs with a gene signature similar to that of ICI. We identified mitoxantrone and thioridazine and tested them in primary, Tam-resistant and genome-edited Y537S ER-expressing BC cells.\n\nResultsMitoxantrone and thioridazine induced ER downmodulation and prevented MCF-7 cell proliferation. Interestingly, while mitoxantrone was toxic for normal breast cells, thioridazine showed preferential activity toward BC cells. Thioridazine also reduced the ER content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ER-expressing BC cells.\n\nConclusionsWe suggest that the modulation of the ER intracellular concentration in BC cells can also be robustly exploited in in silico screenings to identify anti-BC drugs and further demonstrate a re-purposing opportunity for thioridazine in primary and metastatic ET-resistant BC treatment.