Loss of function of BRCA1 caused by inherited mutation and tissuespecific somatic mutation leads to breast and ovarian cancer. Nearly all BRCA1 germ-line mutations involve truncation or loss of the C-terminal BRCT transcriptional activation domain, suggesting that transcriptional regulation is a critical function of the wild-type gene. The purpose of this project was to determine whether there is a link between the role of BRCA1 in transcriptional regulation and its role in tumor suppression. We developed a cell line (in which BRCA1 can be induced) and used microarray analysis to compare transcription profiles of epithelial cells with low endogenous levels of BRCA1 vs. transcription profiles of cells with 2-4-fold higher induced levels of expression of BRCA1. At these levels of expression, BRCA1 did not induce apoptosis. Undirected cluster analysis of six paired experiments revealed 373 genes, the expression of which was altered significantly and consistently by BRCA1 induction. Expression of 62 genes was altered more than 2-fold. BRCA1-regulated genes associated with breast tumorigenesis included the estrogen-responsive genes MYC and cyclin D1, which are overexpressed in many breast tumors; STAT1 and JAK1, key components of the cytokine signal transduction pathway; the extracellular matrix protein laminin 3A; ID4, an inhibitor of DNA-binding transcriptional activators, which in turn negatively regulates BRCA1 expression; and the prohormone stanniocalcin, expression of which is lost in breast tumor cells. Coordinated expression of BRCA1 with ID4 and with stanniocalcin was confirmed in primary breast and ovarian tumors.B RCA1 is a tumor-suppressor gene in which germ-line mutations predispose to breast and ovarian cancer (1, 2). Tumorigenesis in individuals with germ-line BRCA1 mutations requires somatic inactivation of the remaining wild-type allele (3). In breast and ovarian tumors of patients with no BRCA1 germ-line mutation, expression of BRCA1 is reduced also (4-6). BRCA1 null cells are severely aneuploid with unstable karyotypes (7). BRCA1 regulates multiple nuclear processes including DNA repair and recombination, checkpoint control of the cell cycle, and transcription (reviewed in ref. 8). Much of the evidence for involvement of BRCA1 in these processes is based on identification of multiprotein complexes in which BRCA1 is found. BRCA1 associates with RAD51 and BRCA2 in nuclear foci induced by ionizing radiation (9, 10). RAD 51 catalyzes strand exchange during homology-directed repair of DNA double-strand breaks by gene conversion, suggesting a role for BRCA1 in DNA repair by homologous recombination. BRCA1 also associates directly with the MRE11-RAD50-NBS1 complex, which is responsible for end-processing of double-strand breaks (11,12). In addition, BRCA1 is involved in the repair of oxidative DNA damage by transcription-coupled repair (13,14). BRCA1 is found in two large complexes involved in DNA repair and chromatin remodeling. BRCA1 is a component of BASC, a BRCA1-associated genome surveillance complex...