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We analyzed the transcriptomic, proteomic, and phosphoproteomic landscape of tumors harboring\n                    <jats:italic>ESR1<\/jats:italic>\n                    mutations. Here we show that\n                    <jats:italic>ESR1<\/jats:italic>\n                    mutated cancers exhibit a higher mutational burden associated with increased cell proliferation, and display enhanced activation of the mTOR pathway via MTORC1, suggesting an ER-driven amplification of existing oncogenic mechanisms. Analysis of an independent proteomic dataset from breast cancer cell lines further supported a convergence between MTORC1 and ER signaling programs. Integrative multi-omic data analysis incorporating features related to tumor grade, MTORC1 signaling, and\n                    <jats:italic>ESR1<\/jats:italic>\n                    mutations, enabled the development of a predictive signature that distinguishes patients with\n                    <jats:italic>ESR1<\/jats:italic>\n                    mutation and identified those at high risk of recurrence. This study provides insights into the mechanisms underlying tumor aggressiveness and poor clinical outcome modulated by\n                    <jats:italic>ESR1<\/jats:italic>\n                    mutations and highlights the potential of proteogenomic approaches to identify signaling pathways and molecular signatures.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-11096-w","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:04:23Z","timestamp":1791353063000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ESR1 mutations are associated with enhanced MTORC1 signaling in a context-dependent manner"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4845-1084","authenticated-orcid":false,"given":"Tommaso","family":"De Marchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Kuras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lazaro Hiram","family":"Betancourt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4646-5279","authenticated-orcid":false,"given":"Sven","family":"Kjellstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanette","family":"Valcich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2195-0385","authenticated-orcid":false,"given":"Johan","family":"Vallon-Christersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3826-0989","authenticated-orcid":false,"given":"Christian","family":"Brueffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0815-1896","authenticated-orcid":false,"given":"Lao H.","family":"Saal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2889-7169","authenticated-orcid":false,"given":"Johan","family":"Malmstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0262-9083","authenticated-orcid":false,"given":"Emma","family":"Nim\u00e9us","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"11096_CR1","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1016\/S0140-6736(15)61074-1","volume":"386","author":"Early Breast Cancer Trialists\u2019 Collaborative Group (EBCTCG).","year":"2015","unstructured":"Early Breast Cancer Trialists\u2019 Collaborative Group (EBCTCG). 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