Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERalpha in Cells Modeling Primary and Metastatic Breast Cancer

Estrogen receptor expressing breast cancers (BC) are classically treated with endocrinetherapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which astandardized eective therapy is still lacking. Thus, new drugs are required for primary andmetastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approveddrugs, ouabain and digoxin, induce ER degradation and prevent proliferation in cells modelingprimary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERdegradation, which causes the inhibition of 17-estradiol signaling, induces the cell cycle blockade inthe G2 phase, and triggers apoptosis. Remarkably, these eects are independent of the inhibition of theNa/K pump. The antiproliferative eects of ouabain and digoxin occur also in diverse cancer models(i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugsdownregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabainand digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment ofprimary and metastatic BCs.