DKK-1 an immune-suppressive driver in breast cancer

A recent study published in Nature Communications demonstrates that Dickkopf-1 (DKK-1) has a broader role in breast cancer that extends beyond its function as a bone-related biomarker. The publication “Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer,” reports that DKK-1 produced by the tumor stroma can suppress natural killer (NK) cell activity, helping breast tumors evade immune surveillance (1).

DKK-1 an immune-suppressive driver in breast cancer

Breast cancer progression is shaped not only by tumor cells, but also by the surrounding tumor microenvironment. Factors derived from the bone, cancer-associated fibroblasts, immune cells, and soluble mediators can all influence whether immune surveillance succeeds or fails. In this study, the authors identify DKK-1 as a key stromal factor that contributes to an immune-suppressive environment in breast cancer (1).

DKK-1: from Wnt inhibitor to immune modulator

 DKK-1 is classically known as a soluble inhibitor of Wnt/β-catenin signaling. It has long been associated with bone homeostasis, cancer-induced osteolytic bone disease, breast cancer progression, and bone metastasis (2-7).

The new study expands this view by showing that DKK-1 is expressed by tumor cells, cancer-associated fibroblasts, and bone-derived sources in breast cancer models and patient samples. The researchers found that bone-derived DKK-1 contributes to systemic DKK-1 elevation, while cancer-associated fibroblasts contribute to local DKK-1 production at the primary tumor site (1).

This distinction is important: DKK-1 may influence breast cancer both systemically and locally, linking bone biology, tumor stroma, and anti-tumor immunity.

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

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 easily be measured in serum with the  Biomedica DKK-1 ELISA (BI-20413)

• EASY – Direct measurement – no sample pre-dilution
• CONVENIENT – small sample volume (20 µl/well)
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Literature:

1. Evolving functions of Dickkopf-1 in cancer and immunity. Jaschke N, Hofbauer LC, Göbel A, Rachner TD. Cancer Lett. 2020 Jul 10;482:1-7. doi: 10.1016/j.canlet.2020.03.031. Epub 2020 Apr 3. PMID: 32251706.
2. Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer. Lee S, Ricci B, Tran J, Eul E, Ye J, Ren Q, Clever D, Wang J, Wong P, Haas MS, Stewart SA, Ma CX, Fehniger TA, Faccio R Nat Commun. 2025 Jan 30;16(1):1183. doi: 10.1038/s41467-025-56420-w. PMID: 39885132; PMCID: PMC11782527.
3. Dorsomorphin: A novel inhibitor of Dickkopf-1 in breast cancer. Jaschke N, Kleymann A, Hofbauer LC, Göbel A, Rachner TD. Biochem Biophys Res Commun. 2020 Apr 2;524(2):360-365. doi: 10.1016/j.bbrc.2020.01.106. Epub 2020 Jan 27. PMID: 32001001.
4. Dickkopf-1 (Dkk1) protein expression in breast cancer with special reference to bone metastases. Kasoha M, Bohle RM, Seibold A, Gerlinger C, Juhasz-Böss I, Solomayer EF. Clin Exp Metastasis. 2018 Dec;35(8):763-775. doi: 10.1007/s10585-018-9937-3. Epub 2018 Sep 20. PMID: 30238177.
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6. Retrospective Evaluation of Bone Turnover Markers in Serum for the Prediction of Metastases Development in Breast Cancer Patients: A Cohort Study. Kasoha, Findeklee, Nigdelis, Schmidt, Solomayer, Haj Hamoud, Biomedicines (2024) 12 (6), DOI: 10.3390/biomedicines12061201. PMID: 38927408.
7. Association of Wnt Inhibitors, Bone Mineral Density and Lifestyle Parameters in Women with Breast Cancer Treated with Anastrozolе Therapy. Bojanić, K., Bilić Ćurčić, I., Kuna, L., Kizivat, T., Smolic, R., Raguž Lučić, N., Kralik, K., Šerić, V., Ivanac, G., Tucak-Zorić, S., Včev, A., Smolić, M., 2018. J Clin Med 7.PMID:30227689; PMCID: PMC6162798