{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T20:56:01Z","timestamp":1794257761176,"version":"4.9.0"},"reference-count":61,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"813","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/www.science.org\/content\/page\/science-licenses-journal-article-reuse"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,8,27]]},"abstract":"<jats:p>\n                    Neurofibromin\/NF1 is a RAS (rat sarcoma virus) GTPase-activating protein and estrogen receptor (ER) transcriptional corepressor. NF1\n                    <jats:sup>low<\/jats:sup>\n                    status, identified by copy number loss or low mRNA\/protein expression, is associated with endocrine therapy resistance in ~20% of ER\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    (human epidermal growth factor receptor 2) early-stage breast cancers. The identification of targeted treatments for NF1\n                    <jats:sup>low<\/jats:sup>\n                    ER\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    breast cancer is therefore a priority. In this study, proteogenomic analysis of ER\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    breast cancer demonstrated that NF1\n                    <jats:sup>low<\/jats:sup>\n                    tumors exhibited elevated cyclin-dependent kinase 4\/6 (CDK4\/6) activity. In cell lines,\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    deletion had a dual effect on CDK4 activity: first, by promoting ER recruitment to\n                    <jats:italic toggle=\"yes\">CCND1<\/jats:italic>\n                    (cyclin D1), thereby increasing CDK4\u2013cyclin D1 complex formation, and second, by activating C-RAF (rapidly accelerated fibrosarcoma), which drove phosphorylation of the CDK4 activation loop. Preclinical modeling demonstrated that NF1\n                    <jats:sup>low<\/jats:sup>\n                    ER\n                    <jats:sup>+<\/jats:sup>\n                    cancer cells were more sensitive to fulvestrant combined with a CDK4\/6 inhibitor versus fulvestrant alone, with the induction of cell death in vitro and durable tumor regressions in ER\n                    <jats:sup>+<\/jats:sup>\n                    NF1\n                    <jats:sup>low<\/jats:sup>\n                    patient-derived xenograft models in vivo. Furthermore, NF1\n                    <jats:sup>low<\/jats:sup>\n                    ER\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    tumors were more sensitive to neoadjuvant aromatase inhibitor (AI) plus palbociclib than to neoadjuvant AI alone, as indicated by suppression of mRNA-based proliferation scores. These data are consistent with a model whereby ER and RAS coactivation upon NF1 loss can drive CDK4\/6 activity and endocrine therapy resistance but renders NF1\n                    <jats:sup>low<\/jats:sup>\n                    ER\n                    <jats:sup>+<\/jats:sup>\n                    tumors susceptible to CDK4\/6 inhibition. Development of clinical-grade NF1 diagnostics should be prioritized to determine whether NF1\n                    <jats:sup>low<\/jats:sup>\n                    ER\n                    <jats:sup>+<\/jats:sup>\n                    breast cancers should receive adjusted adjuvant treatment recommendations that reflect increased responsiveness to CDK4\/6 inhibition.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adq5492","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T17:58:41Z","timestamp":1756317521000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["NF1-depleted ER\n                    <sup>+<\/sup>\n                    breast cancers are differentially sensitive to CDK4\/6 inhibitors"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6536-4874","authenticated-orcid":true,"given":"Ze-Yi","family":"Zheng","sequence":"first","affiliation":[{"name":"Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1692-5051","authenticated-orcid":true,"given":"Anran","family":"Chen","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9618-6011","authenticated-orcid":true,"given":"Eric J.","family":"Jaehnig","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, 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