BRCA1 transcriptionally regulates genes involved in breast tumorigenesis

Abstract

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...

Genetic networks responsive to sodium butyrate in colonic epithelial cells

“…Previous research has shown that BRCA1 protein increases arrest in the cell cycle progression of cells [24]. In addition, BRCA1 protein is reported to indicate the positively regulated expression of CCND1 [25], PCNA [26], NEK2 [27] and MAD2L1 [28]. In the present cell system, cell cycle-related genes, especially those participating in this genetic network (Fig.…”

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…32,82,83 BRCA1 gene promoter is methylated in 460% of medullary 95,96 and metaplastic 32 breast cancers of basal-like phenotype. Sporadic invasive ductal carcinomas with basal-like phenotype express ID4, a negative regulator of BRCA1, 97,98 at significantly higher levels than grade-matched controls. 32 This mechanism may account for the low levels of BRCA1 expression in sporadic basal-like carcinomas of ductal morphology.…”

Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress

“…In that study, and in a study by Bouras et al (2002), high levels of STC1 expression were found to be associated with estrogen receptor positivity, which is a marker of good prognosis. Furthermore, the tumor suppressors BRCA1 and p53 have both been reported to upregulate STC1 gene expression (Welcsh et al, 2002;Lai et al, 2007). Continued expression of these genes in cancers is usually associated with good prognosis, and this may be explained in part by STC1 acting as a downstream mediator of apoptosis.…”

“…A number of studies, mostly correlative, of mammalian STC1 mRNA and protein expression have ascribed roles to STC1 ranging from angiogenesis (Kahn et al, 2000;Bell et al, 2001), bone and muscle development (Jiang et al, 2000;Filvaroff et al, 2002;Varghese et al, 2002;Yoshiko et al, 2003), inflammation (Iyer et al, 1999;Kanellis et al, 2003), cellular metabolism (McCudden et al, 2002;Ellard et al, 2007) and cancer (Fujiwara et al, 2000;Ismail et al, 2000;Okabe et al, 2001;Welcsh et al, 2002). Establishing the functional importance and relevance of these putative functions has proved difficult; moreover, STC1-null mice housed in standard laboratory conditions have no obvious phenotype (Chang et al, 2005).…”

“…In an in vitro model of wound healing, STC1 expression was found to be rapidly upregulated following provision of serum to serum-starved human fibroblasts (Iyer et al, 1999). Furthermore, STC1 is regulated by the tumor suppressors BRCA1 (Welcsh et al, 2002) and p53 (Lai et al, 2007), both of which play key roles in orchestrating DNA repair and growth arrest, or apoptosis, in response to various cellular stresses.…”