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J. Cell Biol.,
Volume 143, Number 5, November 30, 1998 1329-1339
* Laboratory of Biology of Aging and Department of Geriatrics, University of Geneva; and 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.
Division of Oncology and § Department of Morphology, University of Geneva Medical Center, CH-1226 Geneva, Switzerland
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