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Nevertheless, it remains uncertain whether HER2 signaling affects the effectiveness of CDK4\/6 inhibitor administered in combination with endocrine therapy for HR<jats:sup>+<\/jats:sup>\/HER2-low breast cancer and suitable intervention measures. This study revealed poor efficacy for CDK4\/6 inhibitor combined with endocrine therapy for HR<jats:sup>+<\/jats:sup>\/HER2-low breast cancer in vitro and in vivo models. Secondly, suppression of HER2 gene expression in HR<jats:sup>+<\/jats:sup>\/HER2-low breast cancer cells resulted in significantly improved efficacy for CDK4\/6 inhibitor combined with endocrine therapy. Furthermore, the anti-HER inhibitor neratinib was administered to enhance the effectiveness of CDK4\/6 inhibitor combined with endocrine therapy in HR<jats:sup>+<\/jats:sup>\/HER2-low breast cancer by inhibiting the HER2 pathway and lowering HER2 mRNA expression. Strikingly, neratinib reversed the efficacy of CDK4\/6 inhibitor and endocrine therapy by reducing HER2 mRNA stability in HR<jats:sup>+<\/jats:sup>\/HER2-low breast cancer through the interaction of HER2 3\u2019-UTR region with hsa-miR-23a-5p. Even after reducing neratinib dosage to the standard 1\/2 dose (20\u00a0mg\/kg), it remained highly effective and well-tolerated. This study provides a viable and well-tolerated triple combination therapy for clinical HR<jats:sup>+<\/jats:sup>\/HER2-low breast cancer.<\/jats:p>","DOI":"10.1038\/s41598-024-82137-9","type":"journal-article","created":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T03:29:22Z","timestamp":1735356562000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Neratinib enhances the efficacy of CDK4\/6 inhibitor plus endocrine therapy in HR+\/HER2-low breast cancer cell line ZR-75-1 via hsa-miR-23a-5p"],"prefix":"10.1038","volume":"14","author":[{"given":"Liushan","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianjun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,28]]},"reference":[{"issue":"10","key":"82137_CR1","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1016\/S1470-2045(19)30420-6","volume":"20","author":"M Giuliano","year":"2019","unstructured":"Giuliano, M. et al. 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