Deregulation of p53-MDM2 auto-regulatory pathway in breast carcinoma.

PURPOSE

p53 tumor suppressor protein (17p13.1) regulates critically the cell cycle and thus it is involved in cancer initiation and prevention. The gene is frequently mutated in breast cancer patients and the mutations have been associated with poor prognosis and response rates to chemotherapy. The purpose of this study was to correlate p53 expression with MDM2, a proto-oncogene (12q14.3), which acts as a major negative regulator in p53-MDM2 auto-regulatory pathway.

METHODS

Seventy breast adenocarcinoma cases were included in the study. Sixty tumors were pathologically categorized as invasive ductal adenocarcinomas, whereas the rest of them were diagnosed as pure in situ carcinomas. Immunohistochemistry (IHC) was applied using anti-p53 and anti-MDM2 antibodies in the corresponding tissue sections.

RESULTS

Overexpression of p53 protein was observed in 39/60 (65%) invasive cases, while 40/60 (66.7%) expressed MDM2 protein. Interestingly, in 26/60 (43%) cases a combined p53/ MDM2 co-expression was detected, whereas in 7/60 (11%) a combined loss of expression was identified (overall co-expression: p=0.999). Concerning in situ carcinomas, co-expression of p53/MDM2 was observed in 7/10 (70%) cases.

CONCLUSIONS

MDM2 oncogene overexpression - predominantly due to gene amplification - is a frequent and critical genetic event in both in situ and invasive breast adenocarcinomas. Accumulation of p53 protein in the nucleus of tumor cells harboring mutant p53 - as the result of its overexpression - does not mean necessarily decreased expression of MDM2. MDM2 directly binds to p53 and represses its transcriptional activity promoting p53 degradation. So targeting the molecule, p53's crucial tumor suppressor function is normally regulated.