Physical and functional interactions between LDLR family members and CXCR4 in breast cancer.

C-X-C chemokine receptor type 4 (CXCR4) belongs to the seven-span G protein-coupled receptor family and plays an important role in promoting cancer metastasis. The single-span receptor, low-density lipoprotein receptor-related protein 6 (LRP6) is commonly considered to be a co-receptor of Wnt and plays an indispensable role during animal development. We recently demonstrated that LRP6 directly binds to CXCR4 via its ectodomain and prevents CXCR4-induced breast cancer metastasis. As a result of structural similarity, LRP6 is also categorized within the low-density lipoprotein receptor (LDLR) family that is involved in lipoprotein transport. We therefore explored whether other LDLR family members could interact with CXCR4. Immunoprecipitation and western blotting analysis showed that LDLR and very low-density lipoprotein receptor (VLDLR) physically interacted with CXCR4. Although stromal cell-derived factor 1/CXCR4 signaling was inhibited by LDLR and LRP1, it was promoted by VLDLR, LRP8 and apolipoprotein E, a general agonist of the LDLR family. Furthermore, breast cancer patients with high CXCR4 expression exhibited the worst prognosis only when combined with high levels of VLDLR/LRP8/apolipoprotein E or low expression of LDLR/LRP1, further suggesting distinct positive and negative roles of LDLR family members in regulating CXCR4. Additional members of the LDLR family, SORL1 and LRP2, also showed a negative correlation with CXCR4 in the prognosis of breast cancer patients. The findings of the present study show that the LDLR family can regulate CXCR4, endowing its members with a previously undescribed role, also suggesting their potential as new breast cancer therapeutic targets and prognostic markers.