title: miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors.
abstract: Aromatase inhibitors (AI) have become the first-line endocrine treatment of choice for postmenopausal estrogen receptor-positive (ER(+)) breast cancer patients, but resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer and may contribute to drug resistance. Here, we investigated the link between altered breast cancer metabolism and AI resistance using AI-resistant and sensitive breast cancer cells, patient tumor samples, and AI-sensitive human xenografts. We found that long-term estrogen deprivation (LTED), a model of AI resistance, was associated with increased glycolysis dependency. Targeting the glycolysis-priming enzyme hexokinase-2 (HK2) in combination with the AI, letrozole, synergistically reduced cell viability in AI-sensitive models. Conversely, MCF7-LTED cells, which displayed a high degree of metabolic plasticity, switched to oxidative phosphorylation when glycolysis was impaired. This effect was ER dependent as breast cancer cells with undetectable levels of ER failed to exhibit metabolic plasticity. MCF7-LTED cells were also more motile than their parental counterparts and assumed amoeboid-like invasive abilities upon glycolysis inhibition with 2-deoxyglucose (2-DG). Mechanistic investigations further revealed an important role for miR-155 in metabolic reprogramming. Suppression of miR-155 resulted in sensitization of MCF7-LTED cells to metformin treatment and impairment of 2-DG-induced motility. Notably, high baseline miR-155 expression correlated with poor response to AI therapy in a cohort of ER(+) breast cancers treated with neoadjuvant anastrozole. These findings suggest that miR-155 represents a biomarker potentially capable of identifying the subset of breast cancers most likely to adapt to and relapse on AI therapy.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Bacci
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.affiliation: Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Antony
authors.initials: A
authors.lastname: Fearns
authors.affiliation: Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribas
authors.affiliation: Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Taddei
authors.affiliation: Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pintus
authors.affiliation: Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom. Academic Department of Biochemistry, The Royal Marsden Hospital, London, United Kingdom.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.affiliation: Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Isacke
authors.affiliation: Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Martin
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. Tuscany Tumor Institute (ITT) and Excellence Centre for Research, Transfer and High Education DenoTHE, Florence, Italy. andrea.morandi@unifi.it paola.chiarugi@unifi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. andrea.morandi@unifi.it paola.chiarugi@unifi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morandi
mesh_terms: D000077384:Anastrozole; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004967:Estrogens / Q000235:genetics*; D005260:Female; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006593:Hexokinase / Q000235:genetics; D006801:Humans; D000077289:Letrozole; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D020360:Neoadjuvant Therapy / Q000379:methods; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics*; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004967:Estrogens; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077384:Anastrozole; D000077289:Letrozole; D006593:Hexokinase