Dimethyl fumarate inhibits ZNF217 and can be beneficial in a subset of estrogen receptor positive breast cancers

• Published in: Breast cancer research and treatment Vol. 201; no. 3; pp. 561 - 570
• Main Authors: Sharma, Tanu, Zhang, Yuanjin, Zigrossi, Alexandra, Cravatt, Benjamin F., Kastrati, Irida
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2023; Springer; Springer Nature B.V
• Subjects: Analysis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cancer research; Care and treatment; Cysteine; Dimethyl Fumarate - pharmacology; Dimethyl Fumarate - therapeutic use; ErbB-2 protein; Estrogen; Estrogen receptors; Estrogens; Female; Genetic transcription; Health aspects; Humans; MCF-7 Cells; Medicine; Medicine & Public Health; Oncology; Original Laboratory Investigation; Phenols; Phenotypes; Proteomics; Receptors, Estrogen; Thiols; Trans-Activators - genetics; Trans-Activators - metabolism; Trans-Activators - therapeutic use; ZNF217; Breast cancer; Cysteine succination; Drug action; Dimethyl fumarate; Cancer therapy
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-023-07037-4

Purpose The oncogenic factor ZNF217 promotes aggressive estrogen receptor (ER)+breast cancer disease suggesting that its inhibition may be useful in the clinic. Unfortunately, no direct pharmacological inhibitor is available. Dimethyl fumarate (DMF) exhibits anti-breast cancer activities, in vitro and in pre-clinical in vivo models. Its therapeutic benefits stem from covalent modification of cellular thiols such as protein cysteines, but the full profile of molecular targets mediating its anti-breast cancer effects remains to be determined. Methods ER+breast cancer cells were treated with DMF followed by cysteine-directed proteomics. Cells with modulated ZNF217 levels were used to probe the efficacy of DMF. Results Covalent modification of ZNF217 by DMF identified by proteomics was confirmed by using a DMF-chemical probe. Inhibition of ZNF217’s transcriptional activity by DMF was evident on reported ZNF217-target genes. ZNF217 as an oncogene has been shown to enhance stem-like properties, survival, proliferation, and invasion. Consistent with ZNF217 inhibition, DMF was more effective at blocking these ZNF217-driven phenotypes in cells with elevated ZNF217 expression. Furthermore, partial knockdown of ZNF217 led to a reduction in DMF’s efficacy. DMF’s in vivo activity was evaluated in a xenograft model of MCF-7 HER2 cells that have elevated expression of ZNF217 and DMF treatment resulted in significant inhibition of tumor growth. Conclusion These data indicate that DMF’s anti-breast cancer activities in the ER+HER2+models, at least in part, are due to inhibition of ZNF217. DMF is identified as a new covalent inhibitor of ZNF217.