Purpose: Epidemiologic studies suggested complicated associations between type 2 diabetes mellitus and breast cancer. High-density lipoprotein (HDL) is inversely associated with the risk and mortality of breast cancer. Our study is to determine the different effects of normal and diabetic HDL on breast cancer cell metastasis. Experimental Design: MDA-MB-231 and MCF7 cells were treated with N-HDL, D-HDL, G-HDL, and Ox-HDL. Cell metastasis potency was examined using a tail-vein injection model, and cell adhesion abilities to human umbilical vein endothelial cells (HUVEC) and extracellular matrix (ECM) were determined in vitro. Integrin expression and protein kinase C (PKC) activity were evaluated, and PKC inhibitor was applied. Results: D-HDL dramatically promoted cell pulmonary metastasis (103.6% increase at P < 0.001 for MDA-MB-231 with 1 x 10(5) cell injection; 157.1% increase at P < 0.05 for MCF7 with 4 x 10(5) cell injection) and hepatic metastasis (18.1-fold increase at P < 0.001 for MCF7 with 4 x 10(5) cell injection), and stimulated higher TC-HUVECs adhesion (21.9% increase at P < 0.001 for MDA-MB-231; 23.6% increase at P < 0.05 for MCF7) and TC-ECM attachment (59.9% and 47.9% increase, respectively, for MDA-MB-231 and MCF7, both at P < 0.01) compared with N-HDL. D-HDL stimulated higher integrin (beta 1, beta 2, beta 3, and an) expression on cell surface and induced higher PKC activity. Increased TC-HUVECs and TC-ECM adhesion induced by D-HDL, G-HDL, and Ox-HDL could be inhibited by staurosporine. Conclusions: Our study showed that glycation and oxidation of HDL in diabetic patients could lead to abnormal actions on breast cancer cell adhesion to HUVECs and ECM, thereby promoting metastasis progression of breast cancer. This will largely draw the attention of HDL-based treatments in the diabetes patients with breast cancer. Clin Cancer Res; 18(5); 1246-56. (C)2012 AACR.