Journal
PHARMACOLOGICAL RESEARCH
Volume 193, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2023.106806
Keywords
Molecular pharmacology; Estrogen receptor; Tamoxifen; Thiosemicarbazones
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This study investigates a new class of anti-cancer agents for the treatment of ER-positive breast cancer. These agents inhibit multiple growth factor receptors and down-stream signaling, leading to decreased expression of hormone receptors and key resistance pathways. In vivo experiments demonstrate that these agents effectively inhibit ER-positive breast cancer growth. This represents an innovative non-hormonal, multi-modal therapeutic approach.
The estrogen receptor-alpha (ER-alpha) is a key driver of breast cancer (BC) and the ER-antagonist, tamoxifen, is a central pillar of BC treatment. However, cross-talk between ER-alpha, other hormone and growth factor receptors enables development of de novo resistance to tamoxifen. Herein, we mechanistically dissect the activity of a new class of anti-cancer agents that inhibit multiple growth factor receptors and down-stream signaling for the treatment of ER-positive BC. Using RNA sequencing and comprehensive protein expression analysis, we examined the activity of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), on the expression and activation of hormone and growth factor receptors, co-factors, and key resistance pathways in ER-alpha-positive BC. DpC differentially regulated 106 estrogen-response genes, and this was linked to decreased mRNA levels of 4 central hormone receptors involved in BC pathogenesis, namely ER, progesterone receptor (PR), androgen receptor (AR), and prolactin receptor (PRL-R). Mechanistic investigation demonstrated that due to DpC and Dp44mT binding metal ions, these agents caused a pronounced decrease in ER-alpha, AR, PR, and PRL-R protein expression. DpC and Dp44mT also inhibited activation and down-stream signaling of the epidermal growth factor (EGF) family receptors, and expression of co-factors that promote ER-alpha transcriptional activity, including SRC3, NF-kappa B p65, and SP1. In vivo, DpC was highly tolerable and effectively inhibited ER-alpha-positive BC growth. Through bespoke, non-hormonal, multi-modal mechanisms, Dp44mT and DpC decrease the expression of PR, AR, PRL-R, and tyrosine kinases that act with ER-alpha to promote BC, constituting an innovative therapeutic approach.
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