{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nLMTK3 is a critical modulator of estrogen receptor‐α (ERα) signaling in breast cancer. It phosphorylates ERα, thereby protecting the receptor from proteasomal degradation and enhancing its transcriptional activity by reducing PKC activity and AKT‐mediated phosphorylation while promoting FOXO3 binding to the ESR1 promoter. This regulation is further influenced by microRNAs such as miR‐34a, which directly target LMTK3 to attenuate estrogen‐driven cell proliferation. Importantly, silencing LMTK3 re‐sensitizes tamoxifen‐resistant cells and correlates with improved clinical outcomes, underscoring its role in both intrinsic and acquired endocrine resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its regulation of ERα, LMTK3 exerts pleiotropic oncogenic functions across multiple cancer types. It promotes tumor aggressiveness and metastasis by upregulating integrin subunits via a CDC42/GRB2‐mediated pathway and by controlling receptor trafficking—for example, by phosphorylating components that facilitate Rab14‐dependent movement of Eph receptors, which enhances cell–cell repulsion and dissemination. In the nucleus, LMTK3 associates with KAP1 and, together with PP1α stabilization, mediates chromatin condensation and transcriptional repression of tumor suppressor genes. It also modulates microRNA biogenesis, thereby establishing a feedback loop that fine‐tunes its own expression. Moreover, LMTK3 contributes to therapy resistance by delaying DNA damage responses through reduced ATM activity, influencing cytotoxic drug sensitivity, and by regulating the translation of oncogenic proteins such as KIT in KIT‐mutant cancers. Clinically, elevated LMTK3 levels (including its soluble forms) correlate with advanced disease stage and poor prognosis in a range of malignancies including gastric, colorectal, thyroid, bladder, and non‐small cell lung cancers, while its precise role in prostate cancer remains to be elucidated."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Georgios Giamas, Aleksandra Filipović, Jimmy Jacob, et al. 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