Abstract P5-09-04: Reduction in raf kinase inhibitor protein predicts poor outcomes and correlates with promoter hypermethylation as well as matrix metalloproteinases expression in patients with breast cancer

Abstract

Abstract Background: Invasion and metastasis are the direct causes of mortality in breast cancer patients. Reduction in raf kinase inhibitor protein (RKIP) expression has been shown to be an indicator of metastatic spread in numerous cancers. However, the role of RKIP alteration in the successive steps of breast carcinogenesis and its association with outcome variables has not been well established in breast carcinoma. Materials and Methods: To elucidate the role of RKIP alteration in the successive steps of breast carcinogenesis and its association with outcome variables, immunohistochemical staining with anti-RKIP antibody was performed in a total of 324 patients with 26 normal breasts, 25 usual ductal hyperplasia, 76 ductal carcinoma in situ (DCIS), and 198 invasive breast carcinoma (IBC) using tissue microarray. In addition, we studied the promoter hypermethylation of RKIP as a mechanism for loss of RKIP expression in IBC. To investigate the potential involvement of RKIP in the modulation of matrix metalloproteinases (MMPs) in breast cancer, we also performed immunohistochemical staining for MMP-1, -2, -9, and -13 in IBC. Results: RKIP expression appeared to decrease progressively along the continuum of neoplastic changes from normal breast epithelium to IBC (P < 0.001). Reduced RKIP expression in IBC was significantly higher than in DCIS (P < 0.05). Reduced RKIP expression was significantly associated with the metastatic relapse (P < 0.001). The patients with reduced RKIP expression had a significantly poorer prognosis for disease-free and overall survival than those with normal expression (P < 0.001 and P < 0.001, respectively). Reduced RKIP expression was one of the statistically significant independent risk factors for disease-free survival (P = 0.003). Reduced RKIP expression in IBC was significantly correlated with promoter hypermethylation (P < 0.05). MMP-2 and -9 expressions in IBC with reduced RKIP expression were significantly higher than that in IBC with normal RKIP expression (P < 0.05 and P < 0.01, respectively)). Conclusion: Our results suggest that tumor progression in breast epithelium is accompanied by reduced RKIP expression. Reduced RKIP expression may serve as a new parameter for the prognostic prediction in patients with IBC. In IBC, RKIP promoter hyermethylation may be involved in RKIP gene inactivation and RKIP can control tumor cell invasion and metastasis through regulation of MMPs, particularly MMP-2 and -9. Citation Format: Ji Shin Lee, Min Ho Park, Jung Hang Yoon. Reduction in raf kinase inhibitor protein predicts poor outcomes and correlates with promoter hypermethylation as well as matrix metalloproteinases expression in patients with breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-09-04.