DKK-1 linked to poor prognosis and metastasis in breast cancer

About Dickkopf-1 (DKK-1)  – a  key regulator of the Wnt signaling pathway

DKK-1 is a protein that functions as a key regulator of the Wnt signaling pathway, which is essential for various cellular processes including growth, development, and tissue homeostasis. DKK-1 primarily acts as an antagonist of the Wnt pathway by binding to specific receptors, thereby inhibiting Wnt signaling activity.

The Wnt pathway is a complex and highly conserved signaling cascade that plays a crucial role in regulating cell growth, differentiation, migration, and tissue development. It also plays a critical role in bone biology, particularly in the regulation of bone formation and remodeling as it influences the activity of osteoblasts, the cells responsible for building new bone, and helps maintain bone mass and strength.

DKK-1 linked to poor prognosis and metastasis in breast cancer

DKK-1 a potential biomarker for disease progression in breast cancer

DKK-1 plays a crucial role in breast cancer by modulating the Wnt signaling pathway, which regulates cell proliferation, differentiation, and migration. Abnormal expression of DKK-1 has been detected in breast cancer, with elevated levels often associated with tumor progression and metastasis, especially to the bones. Increased DKK-1 expression has been linked to poorer prognosis and a higher risk of bone metastases, as it affects the tumor microenvironment and bone remodeling processes (1-3). Therefore, DKK-1 is regarded as a potential biomarker for disease progression and a promising target for therapeutic strategies in breast cancer treatment (4).

DKK-1 suppresses NK cell cytotoxicity in breast cancer

 Breast cancer patients with progressive bone metastases exhibit higher levels of DKK-1 and a decreased number of cytotoxic NK cells compared to those with stable disease. Recent findings suggest that DKK1 promotes a tumor-supporting environment by suppressing NK cell activity in breast cancer (6).

Breast cancer is minimally immunogenic, which allows it to evade T cell recognition and results in limited responsiveness to immune checkpoint blockade. Additionally, breast cancer cells can evade NK cell-mediated immune surveillance. Recent findings suggest that DKK-1 promotes a tumor-supporting environment in breast cancer by suppressing NK cell function (7).

Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer .  Lee S et al., 2025; Nat Commun.

Abstract

Mechanisms related to tumor evasion from NK cell-mediated immune surveillance remain enigmatic. Dickkopf-1 (DKK1) is a Wnt/β-catenin inhibitor, whose levels correlate with breast cancer progression. We find DKK1 to be expressed by tumor cells and cancer-associated fibroblasts (CAFs) in patient samples and orthotopic breast tumors, and in bone. By using genetic approaches, we find that bone-derived DKK1 contributes to the systemic DKK1 elevation in tumor-bearing female mice, while CAFs contribute to DKK1 at primary tumor site. Systemic and bone-specific DKK1 targeting reduce tumor growth. Intriguingly, deletion of CAF-derived DKK1 also limits breast cancer progression, without affecting its levels in circulation, and regardless of DKK1 expression in the tumor cells. While not directly supporting tumor proliferation, stromal-DKK1 suppresses NK cell activation and cytotoxicity by downregulating AKT/ERK/S6 phosphorylation. Importantly, increased DKK1 levels and reduced cytotoxic NK cells are detected in women with progressive breast cancer. Our findings indicate that DKK1 represents a barrier to anti-tumor immunity through suppression of NK cells.

DKK-1 can reliably be measured in biological fluids with a conventional ELISA assay.

DKK-1 ELISA Assay Highlights (Cat. No. BI-20413)

• Small sample volume – 10 µl / well
• Direct measurement- no pre-dilution of samples required!
• Reliable – full validation package
• Easy – 6 standards and control included
• Trusted – widely cited in more than 180 publications
• Protocol booklet link

 

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