NF1deficiency drives metabolic reprogramming in ER+ breast cancer

Author:

House Rachel (Rae) J,Tovar Elizabeth A.,Essenburg Curt J.,Dischinger Patrick S.,Ellis Abigail E.,Beddows Ian,Sheldon Ryan D.,Lien Evan C.,Graveel Carrie R.,Steensma Matthew R.

Abstract

ABSTRACTObjectiveNF1is a tumor suppressor gene and its protein product, neurofibromin, is the key negative regulator of the RAS pathway.NF1is one of the top driver mutations in sporadic breast cancer such that 27% of breast cancers exhibit damagingNF1alterations.NF1loss-of-function is a frequent event in the genomic evolution of estrogen receptor (ER)+ breast cancer metastasis and endocrine resistance.Individuals with Neurofibromatosis type 1 (NF) – a disorder caused by germlineNF1mutations – have an increased risk of dying from breast cancer [1–4]. NF-related breast cancers are associated with decreased overall survival compared to sporadic breast cancer. Despite numerous studies interrogating the role of RAS mutations in tumor metabolism, no study has comprehensively profiled theNF1-mutant breast cancer metabolome to define patterns of energetic and metabolic reprogramming. The goals of this investigation were (1) to define the role ofNF1deficiency in estrogen receptor-positive (ER+) breast cancer metabolic reprogramming and (2) to identify potential targeted pathway and metabolic inhibitor combination therapies forNF1-deficient ER+ breast cancer.MethodsWe employed two ER+NF1-deficient breast cancer models: (1) anNF1-mutant MCF7 breast cancer cell line to model sporadic breast cancer, and (2) three distinct,Nf1-deficient rat models to model NF- related breast cancer [1]. IncuCyte proliferation analysis was used to measure the effect ofNF1deficiency on cell proliferation and drug response. Protein quantity was assessed by Western Blot analysis. We then used RNAseq to investigate the transcriptional effect ofNF1deficiency on global and metabolism-related transcription. We measured cellular energetics using Agilent Seahorse XF-96 Glyco Stress Test and Mito Stress Test assays. We performed stable isotope labeling and measured [U-13C]- glucose and [U-13C]-glutamine metabolite incorporation and measured total metabolite pools using mass spectrometry. Lastly, we used a Bliss synergy model to investigateNF1-driven changes in targeted and metabolic inhibitor synergy.ResultsOur results revealed thatNF1deficiency enhanced cell proliferation, altered neurofibromin expression, and increased RAS and PI3K/AKT pathway signaling while constraining oxidative ATP production and restricting energetic flexibility. Neurofibromin deficiency also increased glutamine influx into TCA intermediates and dramatically increased lipid pools, especially triglycerides (TG). Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis.ConclusionsNF1deficiency drives metabolic reprogramming in ER+ breast cancer. This reprogramming is characterized by oxidative ATP constraints, glutamine TCA influx, and lipid pool expansion, and these metabolic changes introduce novel metabolic-to-targeted inhibitor synergies.HIGHLIGHTSNF1deficiency drives metabolic reprogramming in ER+ breast cancer.NF1-driven metabolic reprogramming is characterized by oxidative ATP constraints, glutamine TCA influx, and lipid pool expansion.NF1-deficient ER+ breast cancer cells have increased sensitivity to a combination of RAS and triglyceride synthesis inhibitors.Graphical Abstract

Publisher

Cold Spring Harbor Laboratory

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