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A correction to this article has been published: J. Cell Biol. 144 (5) 1081
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© The Rockefeller University Press, 0021-9525/1998//1329 $5.00
The Journal of Cell Biology, Volume 143, Number 5, , 1998 1329-1339

Article

In Vitro Repression of Brca1-associated RING Domain Gene, Bard1, Induces Phenotypic Changes in Mammary Epithelial Cells



Irmgard Irminger-Finger*, Jesus V. Soriano§, Geneviève Vaudan§, Roberto Montesano§, and André-Pascal Sappino{ddagger}

* Laboratory of Biology of Aging and Department of Geriatrics, University of Geneva; and {ddagger} Division of Oncology and § Department of Morphology, University of Geneva Medical Center, CH-1226 Geneva, Switzerland

BRCA1-associated RING domain (BARD1) was identified as a protein interacting with the breast cancer gene product BRCA1. The identification of tumorigenic missense mutations within BRCA1 that impair the formation of BARD1–BRCA1 complexes, and of BARD1 mutations in breast carcinomas, sustain the view that BARD1 is involved in BRCA1-mediated tumor suppression. We have cloned the murine Bard1 gene and determined that its expression in different tissues correlates with the expression profile of Brca1. To investigate the function of Bard1, we have reduced Bard1 gene expression in TAC-2 cells, a murine mammary epithelial cell line that retains morphogenetic properties characteristic of normal breast epithelium. Partial repression of Bard1, achieved by the transfection of TAC-2 cells with plasmids constitutively expressing ribozymes or antisense RNAs, resulted in marked phenotypic changes, consisting of altered cell shape, increased cell size, high frequency of multinucleated cells, and aberrant cell cycle progression. Furthermore, Bard1-repressed cell clones overcame contact inhibition of cell proliferation when grown in monolayer cultures and lost the capacity to form luminal structures in three-dimensional collagen gels. These results demonstrate that Bard1 repression induces complex changes in mammary epithelial cell properties which are suggestive of a premalignant phenotype.

Key Words: Bard1 • Brca1 • breast cancer • cell cycle • morphogenesis

Abbreviations used in this paper: BRCA1-associated Ring domain gene 1; BARD1, BARD1 gene product; BRCA1, breast cancer gene 1; BRCA1, BRCA1 gene product; DAPI, 4'6-diamidino-2-phenylindole; HGF, hepatocyte growth factor; IGF-I, insulin-like growth factor I; nt, nucleotide; RING, ring finger motif; RT, reverse transcription.


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