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Non-canonical function of transferrin receptor-1 promotes breast cancer metastasis by activating HCK-STAT3-MMP9 signaling

ABSTRACT: Transferrin receptor 1 (TfR-1), a key mediator of cellular iron uptake, is significantly upregulated across a broad spectrum of malignancies, and its overexpression highly correlated with poor clinical outcomes, such as in breast cancer. However, its precise role in breast cancer progression remains unclear. In this study, analysis of clinical samples from breast cancer patients and public databases demonstrated that high level of TfR-1 in breast cancer samples is strongly associated with metastasis. We further verified that elevated TfR-1 enhances the proliferative and metastatic potential of breast cancer cells both in vitro and in vivo. Mechanistically, we uncovered an unexpected protein kinase activity of TfR-1, which directly phosphorylates hematopoietic cell kinase (HCK). Concurrently, TfR-1 activates ubiquitin-specific protease 32 (USP32), thereby stabilizing HCK protein. Subsequently, phosphorylated HCK facilitates the activation of the transcription factor STAT3, resulting in increased expression and secretion of matrix metalloproteinase 9 (MMP9). Moreover, HCK exerts reciprocal phosphorylation on TfR-1, forming a positive feedback loop. Collectively, our findings unravel a novel molecular mechanism underlying TfR-1-mediated metastasis in breast cancer, highlighting the importance of TfR-1’s non-canonical phosphorylation activity beyond its established role in iron transport, and identifying potential therapeutic targets for cancer intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318333 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:The SRC inhibitor PP2 can block CASK nucleus translocation in macrophage under H5N1 infection. Since PP2 is a general inhibitor for Src family kinases (SFKs), which includes nine members (Csk, Yes, Fyn, Fgr, Lck, Hck, Blk, Lyn, and Frk), we aimed to identify the specific member responsible for the nuclear translocation of CASK. First, we examined the expression of SFKs in macrophages (Csk, Fyn, Fgr, and Hck) following H5N1-IAV infection (Fig. 4A). This observation suggests that Hck is the most abundant SFK and may contribute to virus-induced nuclear translocation of CASK. To test this, we generated constitutively active forms of HCK: HCK△513-524 (deletion mutant) and HCK Y499F mutant (YF mutation) [24], then co-transfected them with an EGFP-CASK construct into 293T cells. Immunoprecipitation with anti-GFP mAb, followed by trypsin digestion and LC-MS/MS analysis, revealed that compared to the control group, the phospho/nonphospho ratio at residue Serine 395 (S395) of CASK increased approximately 10-fold (0.008 to 0.072 by HCK△513-524, 0.008 to 0.108 by HCK Y499F), while the other 8 potential phosphorylation sites did not show significant alterations (Table 1). To confirm the phosphorylation of S395 of CASK is required for nuclear translocation, we generated an EGFP-CASK S395A mutant (SA mutation) to prevent CASK phosphorylation. In the absence of HCK Y499F, both the wild type (CASK S395) and mutant (CASK S395A) remained in the cytosol (left two columns, Fig. 4B). In contrast, transfection of HCK Y499F (red color) induced the translocation of wild type CASK (green color) into the nucleus (3rd column from left, Fig. 4B), an effect not observed with the CASK S395A mutant (4th column from left, Fig. 4B). The percentage of nuclear GFP-CASK (60% and 90% in WT and 35% in S395A) resulting from the overexpression of wild type HCK and HCK Y499F is shown in Figure 4C. Thus, we concluded that activated HCK induces the phosphorylation of CASK at Ser395, facilitating its nuclear translocation.

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Non-canonical function of transferrin receptor-1 promotes breast cancer metastasis by activating HCK-STAT3-MMP9 signaling

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