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

Aleksandra Gruslova, Bryan McClellan, Henriette U. Balinda, Suryavathi Viswanadhapalli, Victoria Alers, Gangadhara R. Sareddy, Tim Huang, Michael Garcia, Linda deGraffenried, Ratna K. Vadlamudi, Andrew J. Brenner

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)375-386
Number of pages12
JournalBreast Cancer Research and Treatment
Volume187
Issue number2
DOIs
StatePublished - Jun 2021

Keywords

  • Breast cancer
  • ER stress
  • Endocrine resistance
  • Endoplasmic reticulum
  • Estrogen receptor
  • FASN
  • Fatty acid synthase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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