Amplification of the MDM2 gene in human breast cancer and its association with MDM2 and p53 protein status

Abstract

Oliner et al., 1992). In addition, it is also thought to function as a regulator of p53 function. This stems from evidence that the MDM2 protein forms oligomeric complexes with the p53 protein in vivo and in vitro (Momand et al., 1992;Oliner et al., 1992) and when experimentally overexpressed inhibits the transactivating capability of p53 (Momand et al., 1992). This inhibition is thought to result from the MDM2 protein binding directly to the acidic activation domain of p53, concealing it from the transcriptional machinery (Oliner et al., 1993). Apart from its role as a p53 regulator, MDM2 also has oncogenic properties, as evident from transfection studies in which MDM2 overexpression was found to increase the tumorigenic potential of NIH3T3 and Rat2 cells (Fakharzadeh et al., 1991) and to overcome wild-type p53 suppression of transformed cell growth (Finlay, 1993 Following hybridisation with a [a-32PJdCLTP-labelled human MDM2 cDNA probe (C14-2), the membranes were exposed to intensifying screens for 2-10 days at -70°C. The blots were subsequently reprobed with the pDCCl.65 probe, which

MDM2 protein expression is a negative prognostic marker in breast carcinoma

“…High levels of p53 expression in turn correlate with mutations in the p53 gene and accumulation of mutant protein. 8 It is possible that MDM2 expression in breast carcinoma is not a reflection of a genetic abnormality at the MDM2 locus but instead represents a host response to p53 loss of function; this is similar to the observation in cervical carcinoma that inactivation of Rb and p53 by HPV oncoproteins results in a dramatic increase in production of immunoreactive p16 by the tumour cells. 23,24 If this is the case, MDM2 immunostaining could be a valuable marker of loss of normal p53 function, and used in addition to direct assessment of the p53 gene and/or protein to identify abnormality in this critically important pathway.…”

“…5 Overexpression of MDM2 is described in many human cancers, including breast carcinoma. 1,3,8 Overexpression of MDM2 protein correlates with high grade and was found to be an independent negative prognostic marker in human breast cancer in one study. 9 Other investigators observed that MDM2 overexpression correlates with favourable prognostic parameters such as ER overexpression.…”

Distinctive patterns of Her‐2/neu, c‐myc, and cyclin D1 gene amplification by fluorescence in situ hybridization in primary human breast cancers

“…Mdm2 protein inactivates wild type p53 and leads to its rapid degradation (42,43). Overexpression of mdm2 can impair wild type p53 function, and has been linked with low levels of p53 immunostaining in human breast cancers (44). Viral proteins, and specifically HPV E6, which can accelerate the degradation of p53 protein, has been detected recently in breast cancers from patients who also had HPV infections involving the uterine cervix.…”

Mdm2: keeping p53 under control

“…Leach et al, 1993;Marchetti et al, 1995), overexpression of the protein without gene ampli®cation was also observed (e.g. McCann et al, 1995;Landers et al, 1994). This was due to gene translocation in the mouse plasmacytoma cell line SP2 or enhanced translation in human choriocarcinoma cell lines (Berberich and Cole, 1994;Landers et al, 1994).…”