FASN inhibition as a potential treatment for endocrine-resistant breast cancer

Autor: Bryan Mcclellan, Linda A. deGraffenried, Aleksandra Gruslova, Gangadhara R. Sareddy, Victoria Alers, Andrew Brenner, Ratna K. Vadlamudi, Michael E. Garcia, Suryavathi Viswanadhapalli, Tim Huang, Henriette U. Balinda
Rok vydání: 2021
Předmět:
Zdroj: Breast Cancer Research and Treatment. 187:375-386
ISSN: 1573-7217
0167-6806
DOI: 10.1007/s10549-021-06231-6
Popis: The majority of breast cancers are estrogen receptor (ERα) positive making endocrine therapy a mainstay for these patients. Unfortunately, resistance to endocrine therapy is a common occurrence. Fatty acid synthase (FASN) is a key enzyme in lipid biosynthesis and its expression is commensurate with tumor grade and resistance to numerous therapies. The effect of the FASN inhibitor TVB-3166 on ERα expression and cell growth was characterized in tamoxifen-resistant cell lines, xenografts, and patient explants. Subcellular localization of ERα was assessed using subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by Western blotting after treatment with TVB-3166 with or without the addition of palmitate or BAPTA. TVB-3166 treatment leads to a marked inhibition of proliferation in tamoxifen-resistant cells compared to the parental cells. Additionally, TVB-3166 significantly inhibited tamoxifen-resistant breast tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine-resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB-3166 treatment is mediated through the induction of endoplasmic reticulum stress. Our preclinical data provide evidence that FASN inhibition by TVB-3166 presents a promising therapeutic strategy for the treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine-resistant breast cancer should be considered.
Databáze: OpenAIRE
Externí odkaz: