Subcellular localization of Mdm2 expression and prognosis of breast cancer

Abstract

BACKGROUND: Mouse double minute 2 (Mdm2) is a negative regulator of the tumor suppressor p53. The p53-Mdm2 pathway may play a role in cancer development and prognosis, although the role of p53-Mdm2 in breast cancer remains unclear. METHODS: p53 and Mdm2 expressions were determined by immunohistochemistry of tissue microarrays of 865 breast cancer patients who underwent surgery. Clinicopathological characteristics and survival data were analyzed. Mdm2 expression was categorized into four groups: negative, cytoplasm positive, nucleus positive, and concurrent nuclear and cytoplasm positive (N+&C+). RESULTS: Negative, cytoplasm-positive, nucleus-positive, and N+&C+ expressions of Mdm2 were observed in 59.2, 10.9, 27.8, and 2.1 % of patients, respectively. The N+&C+ group was associated with larger tumor size, higher grade, negativity for estrogen and progesterone receptors, HER2 positivity, high Ki-67 index, p53 positivity, and triple negative breast cancer. p53-positive tumors showed poorer overall survival than p53-negative tumors. The nucleus-positive and N+&C+ groups showed poorer disease-free survival than the negative and cytoplasm-positive groups. In multivariate analysis, nuclear Mdm2 expression including the N+&C+ group was significantly related to poor prognosis. CONCLUSIONS: Concurrent nuclear and cytoplasmic Mdm2 expression was an independent prognostic factor in patients with breast cancer. Subcellular localization of Mdm2 expression should be considered in the evaluation of Mdm2 in breast cancer.