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

SIMPLE SUMMARY: Breast cancer (BC) treatment relies on the detection of the estrogen receptor α (ERα). ERα-expressing BC patients are treated with anti-estrogen drugs (i.e., tamoxifen and fulvestrant). Despite their proven efficacy, these drugs cause serious side effects in a significant fraction of the patients, including both tumor insurgence in secondary organs, and resistant phenotypes, which result in a relapsing disease with scarce treatment options. Thus, new drugs for treatment of primary and metastatic BC (MBC) are needed. Here, we report the characterization of two cardiac glycosides (CGs) (i.e., ouabain and digoxin), approved by the FDA for treatment of heart disease, as novel ‘anti-estrogen’-like drugs. We found that these drugs induce ERα degradation, and prevent the proliferation of cellular models of primary and metastatic BC cells. Remarkably, we discovered that these CGs are activators of the proteasome, and therefore may be repurposed for treatment not only of BC, but also for other proteasome-based diseases. ABSTRACT: Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.