Alternatively spliced MDM2 transcripts in human breast cancer in relation to tumor necrosis and lymph node involvement

Several short forms of alternatively spliced Murine double minute 2 (MDM2) transcripts have recently been shown to correlate with high-grade malignancy in a number of human tumors. We examined the frequency of splice variants and their correlation with clinicopathological features in 60 cases of human breast cancer. Seven short forms coexpressed with wild-type mRNA were detected by nested RT-PCR. Sequencing of all the MDM2 variants demonstrated mRNA splicing which disrupted not only the conserved p53-binding domain but also, further towards the carboxy-terminus, the conserved nuclear localization sequence and/or the acidic and zinc finger domains. There was no significant correlation between the coexpression of splice variants and tumor size, histologic type or hormone (estrogen and progesterone) receptor status. However, cases with spliced MDM2 transcripts tended to be of a more aggressive type with axillary lymph node involvement and extensive necrosis in the tumors. Although the functional significance of MDM2 variants remains obscure, we anticipate that these variants will be confirmed as a novel prognostic marker in human breast cancer.