Identification of estrogen receptor down-regulators for endocrine resistant breast cancer. Issue 224 (November 2022)

• Record Type: Journal Article
• Authors: Li, Yaxin; Orahoske, Cody M.; Urmetz, Shannon M.; Zhang, Wenjing; Huang, Yanmin; Gan, Chunfang; Su, Bin
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 224(2022)
• Publication Date: 2022-11
• Subjects: ER Estrogen receptor -- AIs aromatase inhibitors -- GR glucocorticoid receptor -- Dex dexamethasone -- RT-PCR reverse-transcription polymerase chain reaction -- SDS/PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis -- FBS fetal bovine serum -- PVDF polyvinylidene difluoride -- Ful Fulvestrant -- LTED long-term estrogen deprivation; Breast cancer -- ER -- Endocrine resistance -- Steroidal compounds; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2022.106162
• Languages: English
• ISSNs: 0960-0760

Abstract

Abstract: Resistance to endocrine therapies remains an impediment for the treatment of estrogen receptor (ER) positive breast cancer. ER down regulator Fulvestrant has showed great activity to overcome the endocrine resistance. However, Fulvestrant has poor bioavailability due to the hydrophobicity. Identification of novel ER down regulator is still important. Compounds 172 and 183 are two steroidal compounds with androgen scaffold but significantly down regulated ER in multiple breast cancer cell lines. RT-PCR results indicated that both compounds did not affect ER gene expression. Proteasome inhibitor MG132 could attenuate ER down regulation effect of the compounds, suggesting that the ER down regulation was via ubiquitin-proteasomal pathway. Furthermore, compounds 172 and 183 could downregulate ER in endocrine resistant breast cancer cell model long term estrogen deprivation (LTED) MCF-7 cells. Hydrophobicity of compounds 172 and 183 were determined and showed improved solubility compared to Fulvestrant. All these results suggested that compounds 172 and 183 could be potential lead compounds for drug development for the treatment of endocrine resistance breast cancer. Highlights: Two novel ER down regulators were identified from 184 steroidal compounds. The compounds induce ER degradation via proteasome pathway. The compounds decrease ER in endocrine resistant breast cancer cells. Water solubility of the compounds are much improved than Fulvestrant.