D4-GDI is a key regulator of Rho GTPases that have been implicated in many aspects of tumor progression. Despite its hematopoietic origin, we recently found D4-GDI to be expressed in human breast cancer cell lines. Targeted disruption of D4-GDI in a highly invasive breast cancer cell line inhibited tumor growth and experimental metastasis in a xenograft mouse model. The aim of this study was to investigate D4-GDI expression in primary breast tumors and to assess whether the expression levels of this protein could be associated with disease progression or other established clinical parameters. Following antibody validation, D4-GDI protein expression was assessed by tissue-microarray analysis of two human breast tissue arrays. Clinical parameters such as disease stages and/or hormone receptor status were available. Based on statistical analysis of the data we determined that D4-GDI levels were significantly higher in benign and early stage tumors when compared to normal breast tissues, which was followed by a dramatic decrease in high-grade malignant tumors and metastatic lesions to the lymph nodes. Breast cancer is thought to develop mostly from cells of luminal lineage; interestingly we observed that D4-GDI expression was almost exclusively found in the luminal cells of the ducts but not in the myoepithelial cells at the outer layer. In addition we found that alteration in D4-GDI expression levels resulted in changes in the expression of epithelial-to-mesenchymal transition (EMT) markers, a critical process for cancer progression. D4-GDI expression also appeared to be associated with the status of estrogen receptor (ER) whose deficiency is known to be linked with poor prognosis. These data support an important role for D4-GDI in tumorigenic transformation. Given its reverse relationship with ER status, D4-GDI levels might also provide additional information on the state of cancer progression as well as potential risk of metastasis in ER-negative patients.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A28.