{"doi":"10.1101/2024.09.26.615177","title":"Endocrine persistence in ER+ breast cancer is accompanied by metabolic vulnerability in oxidative phosphorylation","abstract":"Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2-breast tumors induced by neoadjuvant endocrine therapy ( NCT04568616 ). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Mice bearing cell line- and patient-derived xenografts were used to measure the anti-tumor effects of mitochondrial complex I inhibition in the context of endocrine therapy. Pharmacological inhibition of complex I suppressed the tumor-forming potential of persisters and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability in the context of endocrine-sensitive disease. Statement of Significance: Endocrine-tolerant persister cancer cells that survive endocrine therapy can cause recurrent disease. Persister cells exhibit increased energetic dependence upon mitochondria for survival and tumor re-growth potential.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":487375,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":440321,"name":"Mary D. Chamberlin","orcid":"0000-0002-6821-5206","position":1,"is_corresponding":false},{"id":1285993,"name":"Huijuan Yang","orcid":"0000-0001-6168-001X","position":2,"is_corresponding":false},{"id":292416,"name":"Jonathan D. Marotti","orcid":"0000-0002-2181-3698","position":3,"is_corresponding":false},{"id":1052158,"name":"Alyssa M. Roberts","orcid":"0009-0001-7424-3860","position":4,"is_corresponding":false},{"id":1331681,"name":"Melissa M. Carmichael","orcid":null,"position":5,"is_corresponding":false},{"id":465874,"name":"Lauren Cressey","orcid":"0000-0001-8009-573X","position":6,"is_corresponding":false},{"id":1136599,"name":"Christo Philip C. Dragnev","orcid":"0009-0003-7877-8058","position":7,"is_corresponding":false},{"id":6568,"name":"Eugene Demidenko","orcid":"0000-0002-6584-1148","position":8,"is_corresponding":false},{"id":293731,"name":"Riley A. Hampsch","orcid":null,"position":9,"is_corresponding":false},{"id":576353,"name":"Shannon M. Soucy","orcid":"0000-0001-8672-316X","position":10,"is_corresponding":false},{"id":397493,"name":"Fred Kolling","orcid":"0000-0002-6178-9901","position":11,"is_corresponding":false},{"id":377168,"name":"Kimberley S. Samkoe","orcid":"0000-0002-8234-2308","position":12,"is_corresponding":false},{"id":243169,"name":"James V. Alvarez","orcid":"0000-0003-2910-7621","position":13,"is_corresponding":false},{"id":273955,"name":"Arminja N. Kettenbach","orcid":"0000-0003-3979-4576","position":14,"is_corresponding":false},{"id":292418,"name":"Todd W. 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