Uncovering the transcriptomic basis of endoxifen resistance in ER+ breast cancer cells: Insights from bioinformatics analysis

Abstract

Estrogen receptor alpha-positive (ER+) breast cancer remains a major clinical challenge due to the development of de novo and acquired resistance to endocrine therapy. (Z)-endoxifen (hereafter endoxifen), the most abundant active tamoxifen metabolite, has emerged as a promising drug candidate due to its superior anti-estrogenic activity and favorable side effect profile. This study aimed to elucidate the gene signature(s) associated with endoxifen resistance by employing gene expression analysis, expression signature generation, pathway enrichment analysis, and correlation analysis, using PandaOmics, a commercially available target-discovery platform. Changes in gene expression and pathways in resistant cells were compared to those seen in sensitive cells upon endoxifen treatment. Resistant cells were characterized by stronger inhibition of the estrogen response, partial retention of endoxifen's antiproliferative effects, acquired activation of proinflammatory pathways and epithelial-mesenchymal transition (EMT), activation of the mTOR pathway (contrasting with its inhibition in sensitive cells), and elevated levels of PKCβ. These resistance-specific changes may potentially drive an endoxifen resistance phenotype and, therefore, proteins involved in these pathways may be proposed as potential therapeutic targets for overcoming endoxifen resistance in breast cancer.

Keywords: (Z)-endoxifen; Breast cancer; ER+; Estrogen; PKCb1; SERM; Therapy resistance.