title: The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression.
abstract: 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.
authors.affiliation: Department of Pathology and Cell Biology, Institute for Cancer Genetics, Columbia University Medical Center, 1130 Saint Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Shakya
authors.forename: Matthias
authors.initials: M
authors.lastname: Szabolcs
authors.forename: Ellen
authors.initials: E
authors.lastname: McCarthy
authors.forename: Elson
authors.initials: E
authors.lastname: Ospina
authors.forename: Katia
authors.initials: K
authors.lastname: Basso
authors.forename: Subhadra
authors.initials: S
authors.lastname: Nandula
authors.forename: Vundavalli
authors.initials: V
authors.lastname: Murty
authors.forename: Richard
authors.initials: R
authors.lastname: Baer
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D043171:Chromosomal Instability; D019281:Dimerization; D005260:Female; D018390:Gene Targeting; D007150:Immunohistochemistry; D007621:Karyotyping; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity; D010641:Phenotype; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C491163:Bard1 protein, mouse; D044767:Ubiquitin-Protein Ligases