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.
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.
Entities:
Keywords:
Breast cancer; ER stress; Endocrine resistance; Endoplasmic reticulum; Estrogen receptor; FASN; Fatty acid synthase
Authors: Maura N Dickler; Sara M Tolaney; Hope S Rugo; Javier Cortés; Véronique Diéras; Debra Patt; Hans Wildiers; Clifford A Hudis; Joyce O'Shaughnessy; Esther Zamora; Denise A Yardley; Martin Frenzel; Andrew Koustenis; José Baselga Journal: Clin Cancer Res Date: 2017-05-22 Impact factor: 12.531
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Authors: Gabriel N Hortobagyi; Salomon M Stemmer; Howard A Burris; Yoon-Sim Yap; Gabe S Sonke; Shani Paluch-Shimon; Mario Campone; Kimberly L Blackwell; Fabrice André; Eric P Winer; Wolfgang Janni; Sunil Verma; Pierfranco Conte; Carlos L Arteaga; David A Cameron; Katarina Petrakova; Lowell L Hart; Cristian Villanueva; Arlene Chan; Erik Jakobsen; Arnd Nusch; Olga Burdaeva; Eva-Maria Grischke; Emilio Alba; Erik Wist; Norbert Marschner; Anne M Favret; Denise Yardley; Thomas Bachelot; Ling-Ming Tseng; Sibel Blau; Fengjuan Xuan; Farida Souami; Michelle Miller; Caroline Germa; Samit Hirawat; Joyce O'Shaughnessy Journal: N Engl J Med Date: 2016-10-07 Impact factor: 91.245