{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T05:28:11Z","timestamp":1786426091305,"version":"build-2736575974"},"reference-count":133,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017067","name":"Sbarro Health Research Organization","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017067","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03rgj1v74","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["3\/29_25"],"award-info":[{"award-number":["3\/29_25"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Breast cancer (BC) is the most frequently diagnosed malignancy and generally the leading cause of cancer-related mortality among women worldwide. Molecular targeted therapies, including endocrine treatment for hormone-responsive tumors, anti-HER2 agents for HER2-positive tumors and PARP inhibitors (PARPis) for homologous recombination-deficient (HRD) tumors, have significantly improved patient outcomes, but several clinical challenges are still open. The development of acquired resistance strongly limits the long-term efficacy of current treatment strategies, underscoring the necessity to identify novel therapeutic approaches for breast cancer therapy. In this review, we summarize and discuss recently investigated natural compounds with anti-breast cancer activity, ranging from polyphenols, terpenoids, alkaloids, sulfur-containing compounds and the emerging plant-derived extracellular vesicles. We focus on their ability to induce DNA damage or oxidative stress, modulating the DNA damage response (DDR) and interfering with key oncogenic signaling pathways. We also discuss the potential of these compounds to enhance the efficacy of conventional therapies, thereby offering a promising role in overcoming clinical resistance. Despite clinical relevance remains under development and further studies are required; many of the natural compounds examined here appear to effectively target DDR signaling and oncogenic pathways, supporting their potential use in breast cancer therapy.<\/jats:p>","DOI":"10.3390\/ijms27167107","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T09:24:53Z","timestamp":1786353893000},"page":"7107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Products as Modulators of the DNA Damage Response and Oncogenic Signaling in Breast Cancer Therapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1847-0279","authenticated-orcid":false,"given":"Maria","family":"Cuomo","sequence":"first","affiliation":[{"name":"Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4317-4628","authenticated-orcid":false,"given":"Francesco","family":"Errichiello","sequence":"additional","affiliation":[{"name":"Department of Agricultural Sciences, Grape and Wine Science Division, University of Napoli Federico II, 83100 Avellino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Di Meo","sequence":"additional","affiliation":[{"name":"Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8036-3546","authenticated-orcid":false,"given":"Martino","family":"Forino","sequence":"additional","affiliation":[{"name":"Department of Agricultural Sciences, Grape and Wine Science Division, University of Napoli Federico II, 83100 Avellino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Frusciante","sequence":"additional","affiliation":[{"name":"Department of Agricultural Sciences, Grape and Wine Science Division, University of Napoli Federico II, 83100 Avellino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9009-1572","authenticated-orcid":false,"given":"Michelino","family":"De Laurentiis","sequence":"additional","affiliation":[{"name":"Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5959-016X","authenticated-orcid":false,"given":"Antonio","family":"Giordano","sequence":"additional","affiliation":[{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-9956","authenticated-orcid":false,"given":"Luigi","family":"Alfano","sequence":"additional","affiliation":[{"name":"Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115545","DOI":"10.1016\/j.bcp.2023.115545","article-title":"Triple-Negative Breast Cancer: Epidemiology, Molecular Mechanisms, and Modern Vaccine-Based Treatment Strategies","volume":"212","author":"Karim","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1093\/jnci\/djae056","article-title":"The Unique Risk Factor Profile of Triple-Negative Breast Cancer: A Comprehensive Meta-Analysis","volume":"116","author":"Kumar","year":"2024","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Orrantia-Borunda, E., Anchondo-Nu\u00f1ez, P., Acu\u00f1a-Aguilar, L.E., G\u00f3mez-Valles, F.O., and Ram\u00edrez-Valdespino, C.A. (2022). Subtypes of Breast Cancer. 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