Abstract
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.
Highlights
The past decade has seen significant advancement in increasing survival in the management of estrogen receptor alpha (ERα) positive breast cancer
TVB-3166 treatment leads to a marked inhibition of proliferation in tamoxifen-resistant cells compared to the parental cells
We showed that the reduction of ERα expression upon TVB-3166 treatment is mediated through the induction of endoplasmic reticulum stress
Summary
The past decade has seen significant advancement in increasing survival in the management of estrogen receptor alpha (ERα) positive breast cancer. The use of selective estrogen receptor down-regulators and modulators (SERMs) (e.g., fulvestrant, tamoxifen) [1], mTOR inhibitors (e.g. everolimus) [2], aromatase inhibitors (AI) [3], and most recently the use of cyclin-dependent kinase inhibitors, (eg., ribociclib, Palbociclib,and abemaciclib [4,5,6]) have helped to extend the overall survival of the breast cancer patients. They do not offer an enduring cure and all patients will eventually succumb to their disease. There is still a significant need to find additional treatment options that can help to eliminate the mortality associated with metastatic ERɑ positive breast cancer, as well as to identify new therapies that are more effective, less toxic, and impact survival
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