Evaluation of Raf-1 Kinase Inhibitor Protein in Breast Carcinoma and Its Potential Significance.
Paul J Zhang, Jim Culin, Priti Lal, Geza Acs. Hospital of the University of Pennsylvania, Philadelphia; Moffitt Cancer Center, Tampa, FL
Background: Raf-1 kinase inhibitor protein (RKIP) is an inhibitor of the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathway, which regulates fundamental cellular functions such as proliferation, transformation and survival. Recently, RKIP has been recognized as a suppressor of metastasis in experimental models. Decreased RKIP expression was observed in metastatic compared to primary tumors in prostate and breast cancer. However, little is known about its prognostic role in breast cancer.
Design: Samples of well characterized primary invasive ductal carcinoma from 65 patients with follow-up data from 10 to 177 months (mean 93) were assembled to TMA with three 2mm cores representing each case. The TMA section was stained with RKIP antibody (FL-187, 1:100, Santa Cruze) on BondMax autostainer (Leica). RKIP immunoreactivity was semiquantitated for % of positive tumor cells and staining intensity in scale of 0 to 2 (0 as negative, 1 as week and 2 as strong). A score was generated in each case by the product of the % and intensity scale.
Results: Overall, RKIP immunoreactivity was scored from 0 to 200 with median of 75 and mean of 77. Decreased RKIP expression was seen in tumors with high nuclear grade (p=0.006), high mitotic count (p=0.001), ER (p=0.005) and PR negative (p=0.045) status (t-test). The statistics remained significant when cases were divided by score of 80 (one SD above the mean) to high and low RKIP groups on Chi-square test (p values=0.0169, 0.0002, 0.0013 and 0.0164 respectively). No significant difference was detected between tumors with or without nodal or distant metastasis or lymphovascular invasion. There was a strong trend for decreased recurrence free survival in the low RKIP group (p=0.0661, log rank test) but the trend became less obvious for overall survival (p=0.095).
Conclusions: Decreased RKIP expression is associated with adverse pathologic features of the primary tumors such as high mitotic count, high histologic grade and negative ER and PR status. Despite its potential role in metastasis, level of RKIP expression in primary tumors does not correlate with metastatic status of the tumors. Patients with tumors showing low RKIP expression showed a strong trend for decreased recurrence free survival. Although low RKIP expression in tumors showed a weaker trend for decreased overall survival, larger series might be needed to better demonstrate its impact on patient outcome.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 29, Tuesday Afternoon