Transferrin Receptor-1 Drives Breast Cancer Metastasis via Non-Canonical HCK-STAT3-MMP9 Signaling

Transferrin receptor 1 (TfR-1), primarily known for mediating cellular iron uptake, is frequently overexpressed in various malignancies, including breast cancer. Its elevated expression often correlates with poor clinical outcomes, suggesting a role beyond iron metabolism. However, the precise mechanisms by which TfR-1 contributes to breast cancer progression and metastasis, particularly independent of its canonical iron transport activity, have remained largely undefined, representing a critical gap in understanding disease pathology and identifying novel therapeutic targets.

Researchers analyzed breast cancer tissue specimens and public transcriptomic datasets to correlate TfR-1 expression with tumor metastasis. They conducted a series of in vitro cell functional assays to assess TfR-1's impact on proliferation and metastasis, alongside in vivo xenograft tumor metastasis models. Mechanistic investigations involved co-immunoprecipitation, phosphorylation detection, and protein stability assays to delineate the intermolecular regulatory network between TfR-1, Hematopoietic Cell Kinase (HCK), and Ubiquitin Specific Peptidase 32 (USP32).

Clinical data analysis revealed that elevated TfR-1 expression was tightly linked to a metastatic phenotype in breast cancer. Functional experiments confirmed that upregulated TfR-1 robustly boosted the proliferative and metastatic capacity of breast cancer cells in vitro and in vivo. Mechanistically, TfR-1 dual-regulates HCK: it directly induces HCK phosphorylation while simultaneously activating USP32 to prevent HCK protein degradation, thereby sustaining HCK abundance. Activated HCK further triggers STAT3 transcription factor signaling, which drives the upregulation and secretion of matrix metalloproteinase 9 (MMP9).