Felice Maria Accattatis, Luca Gelsomino, Linda Manna, Piercarlo Del Console, Laura Bianchi, Alfonso Carleo, Rossana De Salvo, Lorenzo Arnaboldi, Ludovica Baù, Alberto Corsini, Adele Elisabetta Leonetti, Rocco Malivindi, Marco Fiorillo, Michael P Lisanti, Cinzia Giordano, Daniela Bonofiglio, Sebastiano Andò, Stefania Catalano, Ines Barone
{"title":"Interplay between Leptin and Stearoyl-CoA Desaturase 1 in Estrogen Receptor-Positive Breast Cancer Cells.","authors":"Felice Maria Accattatis, Luca Gelsomino, Linda Manna, Piercarlo Del Console, Laura Bianchi, Alfonso Carleo, Rossana De Salvo, Lorenzo Arnaboldi, Ludovica Baù, Alberto Corsini, Adele Elisabetta Leonetti, Rocco Malivindi, Marco Fiorillo, Michael P Lisanti, Cinzia Giordano, Daniela Bonofiglio, Sebastiano Andò, Stefania Catalano, Ines Barone","doi":"10.1016/j.ajpath.2025.08.009","DOIUrl":null,"url":null,"abstract":"<p><p>Obesity, a global health challenge, contributes to various cancers, including breast cancer. Complex metabolic dysregulation marks the development of both breast cancer and obesity. Here, the interplay between the obesity-derived adipokine leptin (LEP) and stearoyl-CoA desaturase 1 (SCD), a critical enzyme in fatty acid (FA) metabolism, was explored. STRING database analysis reported a significant protein-protein interaction between LEP and SCD. Functional processing of the differentially expressed genes in LEP-treated breast cancer cells revealed a critical involvement of SCD in the interactome of differentially expressed gene-coding proteins. Kaplan-Meier analyses linked LEP/SCD expression to poorer recurrence-free survival in patients with estrogen receptor α luminal A-like breast cancer. Functional studies demonstrated that LEP up-regulated SCD expression in luminal A-like breast cancer cells through LEP receptor-mediated signaling and activation of sterol regulatory element-binding-protein-1 (SREBP1), a key transcription factor modulating SCD gene transcription. Lipidomic profiling showed that SCD inhibition using MF-438 reduced LEP-induced FA desaturation, characterized by a shift from saturated to monounsaturated FAs. SCD inhibition also abolished the LEP-mediated mitochondrial respiration and ATP production. Additionally, LEP-induced oncogenic features, including enhanced growth and motility, were counteracted by pharmacologic/genetic SCD blockade, confirming SCD's role in leptin's protumorigenic effects. This study highlights the LEP-SCD axis as a driver of metabolic and functional alterations in estrogen receptor α-positive breast cancer, providing insights into the obesity-breast cancer link and identifying potential therapeutic targets (ie, SCD) to counter obesity-driven breast cancer progression.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ajpath.2025.08.009","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Obesity, a global health challenge, contributes to various cancers, including breast cancer. Complex metabolic dysregulation marks the development of both breast cancer and obesity. Here, the interplay between the obesity-derived adipokine leptin (LEP) and stearoyl-CoA desaturase 1 (SCD), a critical enzyme in fatty acid (FA) metabolism, was explored. STRING database analysis reported a significant protein-protein interaction between LEP and SCD. Functional processing of the differentially expressed genes in LEP-treated breast cancer cells revealed a critical involvement of SCD in the interactome of differentially expressed gene-coding proteins. Kaplan-Meier analyses linked LEP/SCD expression to poorer recurrence-free survival in patients with estrogen receptor α luminal A-like breast cancer. Functional studies demonstrated that LEP up-regulated SCD expression in luminal A-like breast cancer cells through LEP receptor-mediated signaling and activation of sterol regulatory element-binding-protein-1 (SREBP1), a key transcription factor modulating SCD gene transcription. Lipidomic profiling showed that SCD inhibition using MF-438 reduced LEP-induced FA desaturation, characterized by a shift from saturated to monounsaturated FAs. SCD inhibition also abolished the LEP-mediated mitochondrial respiration and ATP production. Additionally, LEP-induced oncogenic features, including enhanced growth and motility, were counteracted by pharmacologic/genetic SCD blockade, confirming SCD's role in leptin's protumorigenic effects. This study highlights the LEP-SCD axis as a driver of metabolic and functional alterations in estrogen receptor α-positive breast cancer, providing insights into the obesity-breast cancer link and identifying potential therapeutic targets (ie, SCD) to counter obesity-driven breast cancer progression.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.