An Innovative Non-Hormonal Strategy Targeting Redox Active Metals to Down-Regulate Estrogen-, Progesterone-, Androgen- and Prolactin-Receptors in Breast Cancer
Abstract Estrogen receptor-α (ER-α) is a key driver of breast cancer (BC) targeted by tamoxifen. However, tamoxifen resistance is a major problem. An important mechanism of resistance is the activation of EGFR/HER2/HER3 signaling and other hormone receptors (androgen receptor (AR), progesterone receptor (PR), prolactin receptor (PRL-R)) that intrinsically activate ER-α. Hence, therapeutics targeting multiple receptors, rather than ER-α alone, would be extremely useful and may overcome tamoxifen resistance. This study examined the activity of redox-active 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 crucial hormone receptors, their co-factors, and key resistance pathways in ER-α-positive BC. Strikingly, DpC differentially regulated 106 estrogen-response genes with Sankey diagram analysis demonstrating this was linked to decreased mRNA levels of 4 central hormone receptors involved in BC pathogenesis, namelyER,PR,AR, andPRL-R. Mechanistic dissection demonstrated that due to DpC and Dp44mT binding metal ions, these agents caused a pronounced decrease in ER-α, AR, PR, and PRL-R protein expression. Ablation of the metal-binding site in the thiosemicarbazone totally prevented its suppressive activity, demonstrating a unique non-hormonal mechanism. DpC and Dp44mT also inhibited EGFR, HER2, and HER3 activation, their downstream signaling, and the expression of co-factors that promote ER-α transcriptional activity, including SRC3, NF-κB p65, and SP1.In vivo,DpC was highly tolerable and effectively inhibited ER-α-positive BC growth. In conclusion, through a bespoke non-hormonal mechanism targeting redox active metals, Dp44mT and DpC disrupt multiple key inter-receptor interactions between PR, AR, PRL-R, and tyrosine kinases that act with ER-α to promote BC, constituting an innovative therapeutic approach..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 06. Feb. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shehadeh-Tout, Faten [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.02.02.526543 |
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| PPN (Katalog-ID): |
XBI038594951 |
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| 520 | |a Abstract Estrogen receptor-α (ER-α) is a key driver of breast cancer (BC) targeted by tamoxifen. However, tamoxifen resistance is a major problem. An important mechanism of resistance is the activation of EGFR/HER2/HER3 signaling and other hormone receptors (androgen receptor (AR), progesterone receptor (PR), prolactin receptor (PRL-R)) that intrinsically activate ER-α. Hence, therapeutics targeting multiple receptors, rather than ER-α alone, would be extremely useful and may overcome tamoxifen resistance. This study examined the activity of redox-active 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 crucial hormone receptors, their co-factors, and key resistance pathways in ER-α-positive BC. Strikingly, DpC differentially regulated 106 estrogen-response genes with Sankey diagram analysis demonstrating this was linked to decreased mRNA levels of 4 central hormone receptors involved in BC pathogenesis, namelyER,PR,AR, andPRL-R. Mechanistic dissection demonstrated that due to DpC and Dp44mT binding metal ions, these agents caused a pronounced decrease in ER-α, AR, PR, and PRL-R protein expression. Ablation of the metal-binding site in the thiosemicarbazone totally prevented its suppressive activity, demonstrating a unique non-hormonal mechanism. DpC and Dp44mT also inhibited EGFR, HER2, and HER3 activation, their downstream signaling, and the expression of co-factors that promote ER-α transcriptional activity, including SRC3, NF-κB p65, and SP1.In vivo,DpC was highly tolerable and effectively inhibited ER-α-positive BC growth. In conclusion, through a bespoke non-hormonal mechanism targeting redox active metals, Dp44mT and DpC disrupt multiple key inter-receptor interactions between PR, AR, PRL-R, and tyrosine kinases that act with ER-α to promote BC, constituting an innovative therapeutic approach. | ||
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| 700 | 1 | |a Milioli, Heloisa H. |4 aut | |
| 700 | 1 | |a Roslan, Suraya |4 aut | |
| 700 | 1 | |a Jansson, Patric J. |4 aut | |
| 700 | 1 | |a Dharmasivam, Mahendiran |4 aut | |
| 700 | 1 | |a Graham, Dinny |4 aut | |
| 700 | 1 | |a Anderson, Robin |4 aut | |
| 700 | 1 | |a Wijesinghe, Tharushi |4 aut | |
| 700 | 1 | |a Azad, Mahan Gholam |4 aut | |
| 700 | 1 | |a Richardson, Des R. |4 aut | |
| 700 | 1 | |a Kovacevic, Zaklina |4 aut | |
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