Regulation Of Pre-metastatic Niche By DKK1 In Breast Cancer Bone Metastasis

Breast cancer is one of the most common malignant tumors with bone metastasis in the world,and it is difficult to be cured after bone metastasis.Therefore,it is urgent to study the regulation mechanism of bone metastasis in breast cancer.The previous studies in our laboratory found that the pre-metastatic niche of the breast cancer could be regulated by LGR4,thus promoting the bone metastasis.Moreover,we found a significantly decreases of the DKK1 expression levels in the LGR4 knockdown breast cancer cells.DKK1 is a secreted protein rich in cysteine residues,which belongs to the DKK(Dickkopf)family.Studies have shown that DKK1 mainly plays a role by acting on the Wnt signaling pathway in many diseases,such as cancer,bone diseases,rheumatism and other diseases.In order to further clarify the mechanism of DKK1 in bone metastasis,we conducted this study.First,we found that the content of DKK1 in the serum of breast cancer patients with bone metastasis was significantly higher than that of non-bone metastasis patients and the expression of DKK1 in bone metastasis tissues was significantly up-regulated by ELISA detection and immunohistochemical staining respectively.Furthermore,we found a negative correlation between the expression of DKK1 and the survival rate of breast cancer patients through bioinformatics analysis.And then,DKK1 expression was higher in breast cancer cells with stronger bone metastasis capacity at the cellular level.We constructed a mouse model by the method of pre-metastatic niche,and found that the activity of osteoclasts was improved in the bone environment of mice pretreated with the conditioned medium with overexpression of DKK1 tumor cells,which further significantly promote the occurrence of bone metastasis.In vitro,DKK1 could promote the migration of BMM with a concentration gradient,and,in vivo,the content of osteoclast precursor cells was higher in the posterior limb bone of mice pretreated with conditioned medium with overexpression of DKK1 tumor cells.In addition,DKK1 could act on the classical Wnt signaling pathway of BMM,inhibiting the activation ofβ-catenin and promoting the migration of BMM,rather than through non-classical Wnt signaling pathways.In summary,DKK1 from tumor cells may arrive at bone through pre-metastaticniche,inhibiting BMSC differentiate to osteoblast.Recruitment of osteoclastprecursor cells is facilitated through inhibiting the activation of β-catenin,and theactivity of osteoclast is increased by improving the ratio of RANKL/OPG secretedby osteoblasts,which break the balance between osteoblasts and osteoclasts,promoting the development of osteolytic bone metastases.This study provides a newsight for the mechanism of DKK1 promoting bone metastasis of breast cancer,andsupplies a basis for this as a target to treat bone metastasis of breast cancer.