Targeting POLG to Disrupt Breast Cancer Stem Cells | Aging

Aging #Published this #Research paper on August 8, 2026, in Volume 18, titled “Investigating POLG-driven modulation of cancer stemness: a pilot study in breast cancer cells" by #Researchers from the Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Cosenza 87100, Calabria, Italy; Translational Medicine, University of Salford, Salford M5 4WT, UK; Manchester Cell-Matrix Centre, Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Manchester M13 9PL, UK; Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, Rende, CS 87036, Italy; Lunella Biotech, Ottawa K1Z 7K4, ON, Canada; The Institute of Mental Health Research (IMHR), University of Ottawa, The Royal Ottawa Hospital (ROH), Ottawa K1Z 7K4, Ontario, Canada; Département de Médecine, Université Laval, Québec G1V 0A6, QC, Canada. @salforduni #Aging #BreastCancer #StemCells #POLG #OpenAccess #Mitochondria #PeerReviewed #Journal #Publishing #MedEd DOI - https://doi.org/10.18632/aging.206406 Corresponding authors - Federica Sotgia - fsotgia@gmail.com (ORCiD: 0000-0003-2826-4529), Michael P. Lisanti - michaelp.lisanti@gmail.com (ORCiD: 0000-0003-2034-1382) Abstract Mitochondria have emerged as key regulators of breast cancer stem cell (CSC) biology. Mitochondrial metabolic pathways, including oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis, are frequently altered during tumorigenesis, highlighting their role in breast cancer pathogenesis. Since breast CSCs are highly dependent on mitochondrial metabolism, targeting mitochondrial DNA (mtDNA) replication may represent a strategy to impair CSC maintenance. Mitochondrial DNA polymerase-γ (POLG), composed of a catalytic subunit encoded by POLG1 and an accessory subunit encoded by POLG2, is essential for mtDNA replication and repair. In this pilot study, we investigated whether targeting POLG could modulate breast CSC activity. Genetic knockdown of POLG1 and POLG2 in MCF-7 cells resulted in mtDNA depletion, reduced mitochondrial protein expression, impaired energy production, and loss of stemness-related features. To pharmacologically target POLG, we tested Alovudine, a nucleoside reverse transcriptase inhibitor known to act as an off-target POLG inhibitor. In MCF-7 cells, Alovudine reduced clonogenic potential, decreased mitochondrial DNA-encoded protein levels, and lowered oxygen consumption. To further validate these findings, we employed the independent POLG inhibitor Zalcitabine (ddC) in additional breast cancer models. ddC impaired mitochondrial respiration, reduced mammosphere formation, and modulated SOX2 and NANOG expression. Preliminary Kaplan–Meier analyses in a cohort of 458 breast cancer patients showed that high POLG1 expression correlates with worse clinical outcomes, including relapse-free and overall survival. Taken together, these findings suggest that POLG supports mitochondrial function and CSC maintenance, highlighting its potential as a therapeutic target and prognostic biomarker in breast cancer. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.206406 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, breast cancer, cancer stem cells, cancer metabolism, POLG, mitochondrial DNA To learn more about the journal, please visit https://www.Aging-US.com​​ and connect with us on social media at: Bluesky - https://bsky.app/profile/aging-us.bsky.social ResearchGate - https://www.researchgate.net/journal/Aging-1945-4589 X - https://twitter.com/AgingJrnl Facebook - https://www.facebook.com/AgingUS/ Instagram - https://www.instagram.com/agingjrnl/ LinkedIn - https://www.linkedin.com/company/aging/ Reddit - https://www.reddit.com/user/AgingUS/ Pinterest - https://www.pinterest.com/AgingUS/ YouTube - https://www.youtube.com/@Aging-US Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM