C-MPL signaling in breast cancer: molecular mechanisms and therapeutic implications

The thrombopoietin receptor cellular myeloproliferative leukemia (c-MPL), traditionally recognized for its role in hematopoiesis, has recently emerged as a key mediator of breast cancer progression. Aberrant c-MPL signaling activates multiple oncogenic pathways, including Janus kinase/signal transducer and activator of transcription, phosphatidylinositol 3-kinase/protein kinase B, and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK), promoting tumor cell proliferation, survival, metastasis, and maintenance of cancer stem-like populations. Elevated c-MPL expression is associated with aggressive tumor subtypes, poor prognosis, and therapy resistance. In addition to tumor-intrinsic effects, c-MPL modulates the tumor microenvironment by enhancing angiogenesis and fostering immunosuppressive conditions. Therapeutic strategies targeting c-MPL, including monoclonal antibodies, small-molecule inhibitors, and combination approaches, show promise in preclinical studies. Understanding the molecular mechanisms underlying c-MPL signaling and its interactions with the tumor microenvironment may facilitate the development of novel targeted therapies and improve clinical outcomes in breast cancer.