{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T22:07:26Z","timestamp":1778882846143,"version":"3.51.4"},"reference-count":38,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["101055134"],"award-info":[{"award-number":["101055134"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Around 30% of patients with hormone receptor-positive (HR+) breast cancer acquire resistance to endocrine therapy combined with cyclin-dependent kinase 4\/6 inhibitors (CDK4\/6i), which are first-line treatments in metastatic settings. Therefore, we aimed to identify loci associated with resistance to endocrine therapy and CDK4\/6i; this was achieved using retroviral vectors, which randomly insert gene-disrupting elements into the genome, causing gene expression alterations and potentially leading to therapy resistance. ER-positive ZR75.1 breast cancer cells transduced with retroviral vectors were treated with endocrine (tamoxifen, fulvestrant) or CDK4\/6i monotherapies (abemaciclib, palbociclib, ribociclib) or a combination of fulvestrant and ribociclib. DNA was extracted, and virus integration sites (VISs) were characterized according to the detection frequency and read depth using next-generation sequencing (VIS-NGS). Resistance-associated VIS loci were identified when differentially presented in treated samples compared to controls. Well-established tamoxifen resistance genes (BCAR1, BCAR3, EGFR) were detected, enabling the validation of our approach. Thirty-seven VIS loci were associated with resistance to fulvestrant and ribociclib monotherapies. Twenty of these loci were also identified as candidates for resistance to other CDK4\/6i and to fulvestrant and ribociclib combination therapy, including TRPS1 and TRIM24\u2014genes that are involved in resistance to endocrine therapy but have not yet been associated with resistance to CDK4\/6i. The identification of unique and shared resistance-associated loci highlights the complexity of resistance pathways.<\/jats:p>","DOI":"10.3390\/cells15030260","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T10:08:57Z","timestamp":1769681337000},"page":"260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of Resistance Genes in Breast Cancer Cells Treated with Fulvestrant and Ribociclib via Retroviral Screening and Integration Site Sequencing"],"prefix":"10.3390","volume":"15","author":[{"given":"Zhangzan","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corine","family":"Beaufort","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0983-6296","authenticated-orcid":false,"given":"Jean","family":"Helmijr","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Zantboer","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7401-5094","authenticated-orcid":false,"given":"Giada","family":"Rozema","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla","family":"Muritti","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia J.","family":"Whien","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Uijterwegen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5896-8573","authenticated-orcid":false,"given":"Michele","family":"Massimino","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95124 Catania, Italy"},{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico\u2014S. Marco\u201d, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3428-3366","authenticated-orcid":false,"given":"John W. M.","family":"Martens","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1258-9804","authenticated-orcid":false,"given":"Maurice P. H. M.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13045-025-01660-y","article-title":"Global status and attributable risk factors of breast, cervical, ovarian, and uterine cancers from 1990 to 2021","volume":"18","author":"Li","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Carvalho, E., Canberk, S., Schmitt, F., and Vale, N. (2025). 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