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BRCA1 Transcriptionally Regulates Genes Involved in Breast Tumorigenesis

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BRCA1 Transcriptionally Regulates Genes Involved in Breast Tumorigenesis BRCA1 transcriptionally regulates genes involved in breast tumorigenesis Piri L. Welcsh*, Ming K. Lee*, Rachel M. Gonzalez-Hernandez*†, Daniel J. Black*, Mamatha Mahadevappa‡, Elizabeth M. Swisher*, Janet A. Warrington‡, and Mary-Claire King*§ Departments of *Medicine and Genome Sciences and †Pathology, University of Washington, Health Sciences Room K-160, Seattle, WA 98195-7720; and ‡Affymetrix, Inc., Santa Clara, CA 95051 Communicated by Arno G. Motulsky, University of Washington, Seattle, WA, March 28, 2002 (received for review December 3, 2001) Loss of function of BRCA1 caused by inherited mutation and tissue- 17). Overexpression of BRCA1 induces genes in the apoptotic specific somatic mutation leads to breast and ovarian cancer. Nearly pathway (18, 19). Increased expression of BRCA1 leads to repres- all BRCA1 germ-line mutations involve truncation or loss of the sion of estrogen receptor (ER)-mediated transcription (20–22). C-terminal BRCT transcriptional activation domain, suggesting that Our purpose in this project was to determine whether there is a transcriptional regulation is a critical function of the wild-type gene. link between the role of BRCA1 in transcriptional regulation and The purpose of this project was to determine whether there is a link its role in tumor suppression by identifying transcriptional targets between the role of BRCA1 in transcriptional regulation and its role of BRCA1 that are involved in breast tumorigenesis. We developed in tumor suppression. We developed a cell line (in which BRCA1 can an epithelial cell line in which BRCA1 could be induced at modest be induced) and used microarray analysis to compare transcription levels and then used microarray technology to investigate changes profiles of epithelial cells with low endogenous levels of BRCA1 vs. in the cellular transcription profile in response to induction of transcription profiles of cells with 2–4-fold higher induced levels of BRCA1. In six replicate experiments, after induction of BRCA1 expression of BRCA1. At these levels of expression, BRCA1 did not expression levels of 373 genes were altered consistently, 62 of them induce apoptosis. Undirected cluster analysis of six paired experi- at least 2-fold. Among those implicated in breast tumorigenesis are ments revealed 373 genes, the expression of which was altered cyclin D1, JAK1 and STAT1, MYC, and ID4. These experiments also significantly and consistently by BRCA1 induction. Expression of 62 revealed that BRCA1 induction was highly correlated with expres- genes was altered more than 2-fold. BRCA1-regulated genes associ- sion of the extracellular matrix protein laminin A3 (LAMA3) and ated with breast tumorigenesis included the estrogen-responsive with stanniocalcin (STC1), a prohormone whose loss may serve as genes MYC and cyclin D1, which are overexpressed in many breast a marker of breast and ovarian cancer. tumors; STAT1 and JAK1, key components of the cytokine signal transduction pathway; the extracellular matrix protein laminin 3A; Materials and Methods ID4, an inhibitor of DNA-binding transcriptional activators, which in Generation of Cell Lines with Inducible BRCA1 Expression. A full- turn negatively regulates BRCA1 expression; and the prohormone length BRCA1 cDNA was assembled from partial cDNA clones stanniocalcin, expression of which is lost in breast tumor cells. Coor- kindly provided by I. M. Verma (The Salk Institute, La Jolla, CA). dinated expression of BRCA1 with ID4 and with stanniocalcin was Sequence-verified, full-length wild-type BRCA1 was cloned down- confirmed in primary breast and ovarian tumors. stream of the ecdysone-inducible promoter in pIND (Invitrogen). EcR-293 (Invitrogen) is a human embryonal kidney epithelial RCA1 is a tumor-suppressor gene in which germ-line mutations cell line that stably expresses pVgRXR, which encodes a het- Bpredispose to breast and ovarian cancer (1, 2). Tumorigenesis erodimer of the ecdysone receptor and the retinoid X receptor. in individuals with germ-line BRCA1 mutations requires somatic EcR-293 was used to generate stably transfected clonal cell lines inactivation of the remaining wild-type allele (3). In breast and EcR-293 pIND-BRCA1. The EcR-293 cell line was chosen to ovarian tumors of patients with no BRCA1 germ-line mutation, evaluate BRCA1 effects on expression in noncancerous epithelial expression of BRCA1 is reduced also (4–6). BRCA1 null cells are cells, in particular to evaluate the effect of BRCA1 in cells with severely aneuploid with unstable karyotypes (7). BRCA1 regulates modest endogenous levels of BRCA1 expression (Fig. 1). ER status of EcR-293 cells was tested with an ER␣ monoclonal antibody multiple nuclear processes including DNA repair and recombina- (Immunotech, Westbrook, ME). EcR-293 cells are positive for ER␣ tion, checkpoint control of the cell cycle, and transcription (re- (see Fig. 4, which is published as supporting information on the viewed in ref. 8). Much of the evidence for involvement of BRCA1 PNAS web site, www.pnas.org) and hence may provide results in these processes is based on identification of multiprotein com- similar to breast epithelial cells in these expression experiments. plexes in which BRCA1 is found. BRCA1 associates with RAD51 Ideally, experiments would have been carried out in a BRCA1-null and BRCA2 in nuclear foci induced by ionizing radiation (9, 10). breast or ovarian cell line, but from HCC1937 (7), the only such cell RAD 51 catalyzes strand exchange during homology-directed re- line currently available, we were unable to isolate stable clones pair of DNA double-strand breaks by gene conversion, suggesting expressing pVgRXR. Noncancerous breast and ovarian cell lines a role for BRCA1 in DNA repair by homologous recombination. have high endogenous expression of BRCA1 and thus were not BRCA1 also associates directly with the MRE11–RAD50–NBS1 suited for this project. complex, which is responsible for end-processing of double-strand In EcR-293 cells with the pIND-BRCA1 vector, BRCA1 expres- breaks (11, 12). In addition, BRCA1 is involved in the repair of sion was induced by addition of varying concentrations of ponas- oxidative DNA damage by transcription-coupled repair (13, 14). terone A in 100% ethanol. Control lines were generated by trans- BRCA1 is found in two large complexes involved in DNA repair fecting EcR-293 cells with pIND lacking BRCA1. These control and chromatin remodeling. BRCA1 is a component of BASC, a lines were developed to control for the possibility of leaky expres- BRCA1-associated genome surveillance complex that contains sion of BRCA1 in pIND-BRCA1-transfected but uninduced cell proteins implicated in both DNA-damage sensing and repair (15), ͞ lines. Control lines were mock-induced by treating with ethanol and of a large SWI SNF-related complex that has chromatin alone. Growth rates of EcR-293 cells were not affected by induction remodeling capacity (16). BRCA1 is known to be involved in transcriptional regulation in that it acts in concert with the RNA Pol II holoenzyme, transcription factors, acetylases, and deacetylases Abbreviations: ER, estrogen receptor; STC1, stanniocalcin. and their associated proteins CBP͞p300 and CtIP (reviewed in ref. §To whom reprint requests should be addressed. E-mail: [email protected]. 7560–7565 ͉ PNAS ͉ May 28, 2002 ͉ vol. 99 ͉ no. 11 www.pnas.org͞cgi͞doi͞10.1073͞pnas.062181799 Fig. 1. Inducible expression of BRCA1 in kidney epithelial cell line EcR-293. (A) Western analysis of total cell lysates showing induction of BRCA1 protein by increasing concentrations of ponasterone A. BRCA1 was detected by using BRCA1 polyclonal antibody Ab-1 (PharMingen) to residues 768–793 of exon 11. To control for loading, samples were probed also with an actin antibody (I-19, Santa Cruz Biotechnology). Cells were induced with increasing concentrations of ponasterone A in 100% ethanol, and levels of BRCA1 protein were compared. Cells represented in the first lane were mock-induced with ethanol alone. (B) Expression of BRCA1 protein at 0, 4, 8, 12, 24, and 48 h after induction by 10 ␮M ponasterone A. Maximal induction of BRCA1 was seen at 12 h. (C) Modest increase of BRCA1 protein expression in three pIND-BRCA1 clones (ϩ) induced with 10 ␮M ponasterone A and harvested at 12 h. Control (Ϫ) cells contain pIND vector alone. of BRCA1 by 10 ␮M ponasterone A (see Table 3, which is published Dako LSABϩ kit. Samples were counter-stained with methyl as supporting information on the PNAS web site) green. Oligonucleotide Array-Based Expression Profiling. Hybridization Results and Discussion was to HuGeneFL probe arrays (Affymetrix, Santa Clara, CA) Inducible Expression of BRCA1. Induction of BRCA1 protein expres- containing probe sets representing Ϸ6,800 genes (http:͞͞ sion in the experimental system was characterized by Western blot www.netaffx.com͞index2.jsp). The arrays were synthesized by using (Fig. 1). Ponasterone A (10 ␮M) induced BRCA1 protein Ϸ2–4- light-directed combinatorial chemistry as described (23, 24). The fold over endogenous levels (Fig. 1A). At this level of induction, target was labeled and hybridized to probe arrays, washed, stained, maximal BRCA1 protein expression occurred Ϸ12 h after the GENECHIP 3.2 B and scanned as described (25). software (Affymetrix) addition of ponasterone A (Fig. 1 ). Using the conditions described GENETICS was used to scan and quantitatively analyze image data (26). above, we assayed induced BRCA1 protein in three Ecr-293 lines and found BRCA1 protein to be induced Ϸ2–4-fold in each (Fig. Statistical Analyses. To compare signal intensities of cRNA samples 1C). BRCA1 induction at this level did not stimulate apoptosis from BRCA1-induced lines vs. control lines, a Student’s paired t (Table 3). Total RNA was isolated from each clone 16–18 h after statistic and corresponding two-tailed P value were calculated for the addition of ponasterone A. This window was chosen to follow each probe set. The t test had a value of P Ͻ 0.01 for 549 of the 6,800 maximal BRCA1 protein induction and before induced BRCA1 probe sets.
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