title: Inhibition of autophagy as a new means of improving chemotherapy efficiency in high-LC3B triple-negative breast cancers.
abstract: The triple-negative breast cancer (TN BC) subtype is the most aggressive form of invasive BC. Despite intensive efforts to improve BC treatments, patients with TN BC continue to exhibit poor survival, with half developing resistance to chemotherapy. Here we identify autophagy as a key mechanism in the progression and chemoresistance of a subset of TN tumors. We demonstrate that LC3B, a protein involved in autophagosome formation, is a reliable marker of poor prognosis in TN BC, validating this prognostic value at both the mRNA and protein levels in several independent cohorts. We also show that LC3B has no prognostic value for other BC subtypes (Luminal or HER2 BC), thus revealing a specific impact of autophagy on TN tumors. Autophagy is essential for the proliferative and invasive properties in 3D of TN BC cells characterized by high LC3B levels. Interestingly, the activity of the transcriptional co-activator YAP1 (Yes-associated protein 1) is regulated by the autophagy process and we identify YAP1 as a new actor in the autophagy-dependent proliferative and invasive properties of high-LC3B TN BC. Finally, inhibiting autophagy by silencing ATG5 or ATG7 significantly impaired high-LC3B TN tumor growth in vivo. Moreover, using a patient-derived TN tumor transplanted into mice, we show that an autophagy inhibitor, chloroquine, potentiates the effects of chemotherapeutic agents. Overall, our data identify LC3B as a new prognostic marker for TN BC and the inhibition of autophagy as a promising therapeutic strategy for TN BC patients.
authors.affiliation: a Laboratory of Stress and Cancer; Institut Curie ; Paris , France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lefort
authors.forename: Carine
authors.initials: C
authors.lastname: Joffre
authors.forename: Yann
authors.initials: Y
authors.lastname: Kieffer
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Givel
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bourachot
authors.forename: Giulia
authors.initials: G
authors.lastname: Zago
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
authors.forename: Didier
authors.initials: D
authors.lastname: Meseure
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.forename: Jacques
authors.initials: J
authors.lastname: Camonis
authors.forename: Fatima
authors.initials: F
authors.lastname: Mechta-Grigoriou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis* / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D008869:Microtubule-Associated Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen
keywords: 3-dimensional culture; 3D, 3-dimensions; AC, adriamycin and cyclophosphamide; ACTB, actin, β; AP2A1/adaptin, adaptor-related protein complex 2, α 1 subunit; ATG, autophagy-related; BC, breast cancer; BECN1, Beclin 1, autophagy related; BafA1, bafilomycin A1; Ctrl, control; DFS, disease-free survival; EBSS, Earle's balanced salt solution; ERBB2/HER2, v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HScore, histological scoring; IHC, immunohistochemistry; LC3B; Lum, Luminal; MAP1LC3B/LC3B, microtubule-associated protein one light chain 3 β; OS, overall survival; PDX, patient-derived xenografted tumor; TCGA, The Cancer Genome Atlas; TGI, tumor growth inhibition; TN BC, triple-negative breast cancer; YAP1; YAP1, Yes-associated protein 1; autophagy; breast cancers; i.p., intra-peritoneal; prognosis; response to treatment; sem, standard error of mean; three-MA, 3-methyladenine