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

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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Author notes

  1. Aleksandra Gruslova and Bryan McClellan have contributed equally to this work.

Authors and Affiliations

  1. UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX, USA

    Aleksandra Gruslova, Henriette U. Balinda, Victoria Alers, Tim Huang, Michael Garcia & Andrew J. Brenner

  2. Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, USA

    Suryavathi Viswanadhapalli, Gangadhara R. Sareddy & Ratna K. Vadlamudi

  3. The University of Texas At Austin, Austin, TX, USA

    Bryan McClellan & Linda deGraffenried

  4. South Texas Research Facility, University of Texas Health San Antonio, STRF 2.208.58403 Floyd Curl Dr, San Antonio, TX, 78229, USA

    Andrew J. Brenner

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  1. Aleksandra Gruslova
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Correspondence to Andrew J. Brenner.

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Gruslova, A., McClellan, B., Balinda, H.U. et al. FASN inhibition as a potential treatment for endocrine-resistant breast cancer. Breast Cancer Res Treat 187, 375–386 (2021). https://doi.org/10.1007/s10549-021-06231-6

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  • DOI: https://doi.org/10.1007/s10549-021-06231-6

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