Abnormal expression of MDM-2 in breast carcinomas

Abstract

MDM-2 is a cellular oncoprotein that binds to the p53 protein and abrogates its growth-suppressing function. At least seven MDM-2 mRNAs and five proteins (p90, p85, p76, p74, and p57) have been reported in tissue culture. MDM-2 gene amplification occurs in human sarcomas and high-grade gliomas. MDM-2 overexpression without gene amplification has been reported in leukemias and lymphomas. Here we report MDM-2 mRNA overexpression in 24 (73%) out of 33 cases of human breast carcinoma as compared with normal breast tissue. The MDM-2 overexpression was seen in the absence of MDM-2 gene amplification. MDM-2 protein expression was studied by western blot analysis in 21 of these cases of carcinoma. We found complete concordance between MDM-2 mRNA overexpression and MDM-2 protein levels. MDM-2 proteins were overexpressed in 15 of 21 breast carcinoma tissue samples but not in normal breast tissue controls. Ten of these fifteen cases overexpressed MDM-2 p57 protein, two cases overexpressed both p57 and p90, and three cases overexpressed only p90. MDM-2 overexpression was confirmed by immunohistochemistry. p53 overexpression was also studied by immunohistochemistry, 69% of breast carcinomas that overexpressed the MDM-2 mRNA had detectable nuclear p53 protein. These findings demonstrate that MDM-2 oncoprotein expression is altered in primary human breast carcinomas at both mRNA and protein levels. In addition, our results suggest that MDM-2 p57 protein represents the main MDM-2 protein altered in breast carcinomas.

Tumor suppressor genes in normal and malignant hematopoiesis

“…Overexpression due to hitherto unknown reasons might play a role in some hematopoietic malignancies. MDM-2 has been documented to be highly expressed in 40% cases of AML (Faderl et al, ;Bueso-Ramos et al, 1993;Seliger et al, 1996). A small study of MDS found MDM-2 to be highly expressed in ®ve out of seven samples (Bueso-Ramos et al, 1993), a large study found normal levels of the protein in 21 cases of MDS .…”

“…MDM-2 has been documented to be highly expressed in 40% cases of AML (Faderl et al, ;Bueso-Ramos et al, 1993;Seliger et al, 1996). A small study of MDS found MDM-2 to be highly expressed in ®ve out of seven samples (Bueso-Ramos et al, 1993), a large study found normal levels of the protein in 21 cases of MDS . MDM-2 was reported to be frequently (450%) overexpressed in multiple myeloma (Lai et al, 1998) and high grade NHL (Finnegan et al, 1994;Moller et al, 1999) and moderately frequently in low grade NHL, CLL (Bueso-Ramos et al, 1993;Watanabe et al, 1994) and childhood ALL (Zhou et al, 1995;Marks et al, 1997;Gustafsson and Stal, 1998).…”

“…Overexpression of MDM-2 as a mechanism of p53 inactivation was initially described in human sarcomas as a result of gene ampli®cation (Oliner et al, 1992). Gene ampli®cation of MDM-2 was not detected in leukemias and NHL (Bueso-Ramos et al, 1993;Schottelius et al, 1994;Ridge et al, 1994), advanced MDS (Preudhomme et al, 1993) or NHL (Kawamata et al, 1996), but a recent report described MDM-2 gene ampli®cation in four out of six cases of Hodgkin's lymphoma (Kupper et al, 2001). Overexpression due to hitherto unknown reasons might play a role in some hematopoietic malignancies.…”

An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2

“…However, recent data suggest that overproduction of HDM2 may result from mechanisms other than gene ampli®cation and include chromosomal translocations (Berberich and Cole, 1994), increased levels of hdm2 mRNA (Bueso-Ramos et al, 1993;Watanabe et al, 1994), or enhanced translation (Landers et al, 1994;Capoulade et al, 1998).…”

The contribution of the RING finger domain of MDM2 to cell cycle progression

“…Over-expression of the MDM2 protein confers oncogenic properties to NIH3T3 cells (Fakharzadeh et al, 1991), immortalizes rat embryonic ®broblasts and transforms them in cooperation with activated ras (Finlay, 1993). Approximately 5 ± 10% of all human tumours contain overexpressed MDM2, suggesting that it contributes to tumour development and/or tumour progression (Bueso-Ramos et al, 1993JuvenGershon and Oren, 1999;Oliner et al, 1992). MDM2 is believed to be oncogenic due to negative regulation of the p53 tumour suppressor gene product (JuvenGershon and Oren, 1999).…”