Women with germ-line mutations of the BRCA1 tumor suppressor gene are highly susceptible to breast and ovarian cancer. The protein product of BRCA1 is involved in a broad spectrum of biological processes and interacts with many diverse proteins. One of these, BARD1, associates with BRCA1 to form a heterodimeric complex that is enzymatically active as an ubiquitin E3 ligase. Although the BRCA1/BARD1 heterodimer has been implicated in several aspects of BRCA1 function, its role in tumor suppression has not been evaluated. To address this question, we generated mouse strains carrying conditional alleles of either Bard1 or Brca1 and used Cre recombination to inactivate these genes in mammary epithelial cells. Significantly, the conditional Bard1-and Brca1-mutant mice developed breast carcinomas that are indistinguishable from each other (and from those of double conditional Bard1/Brca1-mutant animals) with respect to their frequency, latency, histopathology, and cytogenetic features. Reminiscent of the basal-like breast carcinomas seen in human BRCA1 mutation carriers, these tumors are ''triple negative'' for estrogen and progesterone receptor expression and HER2/neu amplification. They also express basal cytokeratins CK5 and CK14, have an elevated frequency of p53 lesions, and display high levels of chromosomal instability. The remarkable similarities between the mammary carcinomas of Bard1-, Brca1-, and Bard1/Brca1-mutant mice indicate that the tumor suppressor activities of both genes are mediated through the BRCA1/BARD1 heterodimer.basal-like breast cancer ͉ mammary carcinogenesis G erm-line mutations of the BRCA1 tumor suppressor gene serve as predisposing lesions in women with a familial susceptibility to breast and ovarian cancer (1). The breast tumors of BRCA1 mutation carriers typically display ''basal-like'' features that define a subtype of breast cancer with a distinct histopathology and gene expression profile (2-5). Basal-like breast carcinomas have been described as ''triple negative'' because they often lack expression of estrogen receptor (ER) ␣, the progesterone receptor (PR), and the HER2/neu protooncogene. Patients with basal-like breast cancer face a poor prognosis and reap little benefit from current therapies that target ER-or HER2-expressing tumor cells.Although the mechanism of BRCA1-mediated tumor suppression is unclear, its protein product has been implicated in a remarkably broad range of cellular processes, some of which serve to maintain genome stability (6-8). Consistent with its pleiotropic nature, the BRCA1 polypeptide has been reported to interact with a large and diverse group of proteins. One of these, BARD1, is structurally related to BRCA1 in that it harbors an N-terminal RING motif and two C-terminal BRCT domains (9), and the heterodimer complex formed by these proteins functions as a potent ubiquitin E3 ligase (10). Although it has been proposed that the tumor suppression activity of BRCA1 is mediated by the BRCA1/BARD1 heterodimer (11), experimental evidence to support this h...

Cre-mediated deletion of exons 3 and 4 of the mouse Brca2 gene occurring speci®cally in mammary epithelial cells of conditional female mutants carrying a combination of loxP-modi®ed and null Brca2 alleles resulted in a high incidence (77%) of breast tumors that were often palpable and developed in one or more glands after long latency (time for median tumor-free survival of *1.4 years; total of 40 tumors in 20 animals). These invasive adenocarcinomas were histologically quite uniform, exhibiting predominantly a solid, nodular tumor pattern with very few variants, in striking contrast to the morphological heterogeneity of analogous Brca1-associated tumors. The karyotypes of tumor cells lacking Brca2 had various chromosomal aberrations and ranged from diploid to hypertetraploid, but this wide variability was incongruous with the histological appearance of carcinomas that was comparable between specimens. The implications of these observations in the context of models positing that Brca2 is involved in the maintenance of genomic stability are discussed. Oncogene (2001) 20, 3937 ± 3948.

B-cell post-transplant lymphoproliferative disorders (PTLD) are classified as early lesions, polymorphic lymphomas (P-PTLD) and monomorphic lymphomas (M-PTLD). These morphologic categories are thought to reflect a biologic continuum, although supporting genetic data are lacking. To gain better insights into PTLD pathogenesis, we characterized the phenotypes, immunoglobulin (Ig) gene alterations and non-Ig gene (BCL6, RhoH/TTF, c-MYC, PAX5, CIITA, BCL7A, PIM1) mutations of 21 PTLD, including an IM-like lesion, 8 P-PTLD and 12 M-PTLD. Gene expression profile analysis was also performed in 12 cases. All PTLD with clonal Ig rearrangements showed evidence of germinal centre (GC) transit based on the analysis of Ig and BCL6 gene mutations, and 74% had a non-GC phenotype (BCL6 +/- MUM1+). Although surface Ig abnormalities were seen in 6/19 (32%) PTLD, only three showed 'crippling' Ig mutations indicating other etiologies for loss of the B-cell receptor. Aberrant somatic hypermutation (ASHM) was almost exclusively observed in M-PTLD (8/12 vs. 1/8 P-PTLD) and all three recurrent cases analysed showed additional mutations in genes targeted by ASHM. Gene expression analysis showed distinct clustering of PTLD compared to B-cell non-Hodgkin lymphomas (B-NHL) without segregation of P-PTLD from non-GC M-PTLD or EBV+ from EBV- PTLD. The gene expression pattern of PTLD appeared more related to that of memory and activated B-cells. Together, our results suggest that PTLD represent a distinct type of B-NHL deriving from an antigen experienced B-cell, whose evolution is associated with accrual of genetic lesions.