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

Claudia Busonero, Stefano Leone, Fabrizio Bianchi, Filippo Acconcia

Research output: Contribution to journalArticle

Abstract

Purpose: Most breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (ICI 182,780; ICI). Unfortunately, a high fraction of ET treated women relapses and becomes 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 modulation of the intracellular ERα content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ERα content in BC cells. Methods: We 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 ERα-expressing BC cells. Results: We found that mitoxantrone and thioridazine induced ERα downmodulation and prevented MCF-7 BC cell proliferation. Interestingly, while mitoxantrone was found to be toxic for normal breast epithelial cells, thioridazine showed a preferential activity towards BC cells. Thioridazine also reduced the ERα content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ERα expressing BC cells. Conclusions: We suggest that modulation of the intracellular ERα concentration in BC cells can be exploited in in silico screens to identify anti-BC drugs and uncover a re-purposing opportunity for thioridazine in the treatment of primary and metastatic ET resistant BCs.

Original languageEnglish
Pages (from-to)677-686
Number of pages10
JournalCellular Oncology
Volume41
Issue number6
DOIs
Publication statusPublished - Dec 1 2018

Keywords

  • Breast cancer
  • Degradation
  • Estrogen receptor
  • Mitoxantrone
  • Thioridazine
  • Y537S

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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