Reduction of Raf-1 Kinase Inhibitor Protein (rkip) Expression in Breast Cancer Metastases

نویسندگان

  • Suzanne Hagan
  • Fahd Al Mulla
  • Elizabeth Mallon
  • Karin Oien
  • Rhona Ferrier
  • Barry Gusterson
  • Jorge J Curto
  • Walter Kolch
چکیده

INTRODUCTION Raf-1 Kinase Inhibitor Protein (RKIP) is physiological endogenous inhibitor of the Raf-MEK-ERK pathway (1). Alterations in this pathway are associated with tumor development and progression. Recent work has shown that RKIP is diminished in some metastatic cancers. We studied lymph node negative cancers and node-positive patients, with paired lymph node metastases and show highly significant downregulation of RKIP in lymph node metastases (p<0.001), compared to matched primary tumors. No significant correlations were found between RKIP expression and established clinico-pathological prognostic indicators, suggesting that RKIP expression is an independent marker of breast cancer lymph node metastases. METHOD Paraffin-embedded tumors from 103 patients (52 node-negative and 51 node-positive patients, with 51 paired lymph node metastases) underwent immunohistochemical staining for RKIP using the streptavidin–biotin method and the chromogen 3, 3diaminobenzidine. Paraffin-embedded sections of prostate cancer served as positive RKIP controls and omission of primary antibody served as negative controls. RKIP expression levels were scored using the visual grading system. RESULTS All of the primary breast tumors analyzed in this study demonstrated RKIP immunoreactivity (except for one node-negative tumor), and the distribution of RKIP was found to be mainly cytoplasmic. RKIP expression was predominantly moderate in node-positive tumors (31/51 cases, 60.8%) and was weakly positive in 20/51 (39.2%) cases. By contrast, in the matched lymph node metastases RKIP expression was considerably diminished and, in some cases, was entirely absent (9/51, 17.7%), and this decrease was found to be highly significant (p=0.000003; Fig 1). In total, 30/51 (58.8%) of lymph node cases were weakly positive and 12/51 cases (23.5%) were moderately positive for RKIP expression. Of the node-negative tumors, RKIP expression was moderate in 37/52 cases (71.2%), weakly positive in 14/52 cases (26.9%) and negative in 1/52 cases (1.9%). A trend was observed for more intense RKIP staining of node-negative breast tumors than for node-positive tumors, but this was not found to be statistically significant.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis.

PURPOSE Raf-1 kinase inhibitor protein (RKIP) was originally identified as the first physiologic inhibitor of the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathway. This pathway regulates fundamental cellular functions, including those that are subverted in cancer cells, such as proliferation, transformation, survival, and metastasis. Recently, RKIP...

متن کامل

Reduction in Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal-regulated kinase signaling in melanoma cell lines.

Mutations in the Raf signaling pathway are known to play a pivotal role in the progression of malignant melanoma. In this study, we provide evidence that the Raf-1 kinase inhibitory protein (RKIP) and its effects on Raf-1-mediated activation of mitogen-activated protein/extracellular signal-regulated kinase kinase are important for the metastatic potential of malignant melanoma. Screening nine ...

متن کامل

Effects of raf kinase inhibitor protein expression on metastasis and progression of human breast cancer.

Raf kinase inhibitor protein (RKIP) has been shown to be a metastasis suppressor in many kinds of malignant tumors. But its function in breast cancer was not yet clarified completely. We detected RKIP expression in clinical samples of primary breast cancer, breast cancer metastases, and in different breast cancer cells. Compared with the normal breast epithelia, benign breast epithelia, or in s...

متن کامل

RKIP Inhibits Local Breast Cancer Invasion by Antagonizing the Transcriptional Activation of MMP13

Raf Kinase Inhibitory Protein or RKIP was initially identified as a Raf-1 binding protein using the yeast 2-hybrid screen. RKIP inhibits the activation phosphorylation of MEK by Raf-1 by competitively inhibiting the binding of MEK to Raf-1 and thus exerting an inhibitory effect on the Raf-MEK-Erk pathway. RKIP has been identified as a metastasis suppressor gene. Expression of RKIP is low in can...

متن کامل

Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer.

BACKGROUND Diminished expression of Raf kinase inhibitor protein (RKIP), an inhibitor of the Raf signaling cascade, promotes prostate cancer (PCa) metastasis in a murine model, suggesting that it is a metastasis suppressor gene. However, the prognostic significance of RKIP expression and its association with metastasis in PCa patients is unknown. METHODS To investigate RKIP protein expression...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره   شماره 

صفحات  -

تاریخ انتشار 2005