By applying a novel native top‑down proteomics (nTDP) platform to breast cancer cell models (including EGFR-overexpressing, estrogen receptor therapy–resistant variants), the authors directly profiled intact protein assemblies up to ~70 kDa. They detected ~104 complexoforms across 17 protein complexes, uncovering EGFR-triggered dissociation of NUTF2 dimers and pinpointing PTMs at K4 and K55 that modulate ER signaling inhibition. This work illuminates how specific proteoform combinations control endocrine response and highlights new avenues for proteoform‑targeted therapeutics.