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A Cell-Type-Specific Transcriptional Network Required for Estrogen Regulation of Cyclin D1 and Cell Cycle Progression in Breast Cancer

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A Cell-Type-Specific Transcriptional Network Required for Estrogen Regulation of Cyclin D1 and Cell Cycle Progression in Breast Cancer Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer Jérôme Eeckhoute, Jason S. Carroll, Timothy R. Geistlinger, Maria I. Torres-Arzayus, and Myles Brown1 Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA Estrogen stimulates the proliferation of the most common type of human breast cancer that expresses estrogen receptor ␣ (ER␣) through the activation of the cyclin D1 (CCND1) oncogene. However, our knowledge of ER␣ transcriptional mechanisms remains limited. Hence, it is still elusive why ER␣ ectopically expressed in ER-negative breast cancer cells (BCC) is functional on ectopic reporter constructs but lacks activity on many endogenous target genes, including CCND1. Here, we show that estradiol (E2) stimulation of CCND1 expression in BCC depends on a novel cell-type-specific enhancer downstream from the CCND1 coding region, which is the primary ER␣ recruitment site in estrogen-responsive cells. The pioneer factor FoxA1 is specifically required for the active chromatin state of this enhancer and as such is crucial for both CCND1 expression and subsequent cell cycle progression. Interestingly, even in BCC, CCND1 levels and proliferation are tightly controlled by E2 through the establishment of a negative feedforward loop involving the induction of NFIC, a putative tumor suppressor capable of directly repressing CCND1 transcription. Taken together, our results reveal an estrogen-regulated combinatorial network including cell-specific cis- and trans-regulators of CCND1 expression where ER␣ collaborates with other transcription factors associated with the ER-positive breast cancer phenotype, including FoxA1 and NFIC. [Keywords: Breast cancer; estrogen receptor; cyclin D1; transcription; enhancer; chromatin] Supplemental material is available at http://www.genesdev.org. Received May 2, 2006; revised version accepted July 26, 2006. Cyclin D1 (CCND1) belongs to the family of D-type cy- mary gland was confirmed by genetically modified clins, which regulate G1–S cell cycle progression (Quelle mouse models where CCND1 overexpression leads to et al. 1993). CCND1 acts through activation of cyclin- the development of mammary carcinoma (Wang et al. dependent kinases (cdks) that phosphorylate and inacti- 1994), while CCND1 ablation results in mice resistant to vate the retinoblastoma protein. However, recent find- cancer induced by several oncogenes (Yu et al. 2001). The ings indicate that CCND1 could also promote cell cycle CCND1-null mice also showed defective postnatal progression through cdk-independent mechanisms, such mammary development revealed by a lack of prolifera- as interaction with and modulation of transcription fac- tion of alveolar epithelial cells in response to the sex tor activities (for reviews, see Ewen and Lamb 2004; Ar- steroid milieu of pregnancy (Fantl et al. 1995; Sicinski et nold and Papanikolaou 2005). CCND1 is a well recog- al. 1995). nized oncogene that is amplified and/or overexpressed in Indeed, CCND1 expression is induced in mammary a substantial proportion of human cancers including epithelial cells by estrogen and progesterone (Sutherland parathyroid adenoma, colon cancer, lymphoma, mela- et al. 1998), which act through transcription factors of noma, prostate cancer, and breast cancer (Ewen and the nuclear receptor superfamily; i.e., the estrogen recep- Lamb 2004). More specifically, CCND1 is one of the tors (ER) ␣ and ␤ and the progesterone receptors (PR) A most commonly overexpressed genes in human breast and B. Over two-thirds of human breast cancers express cancer (up to 50% of breast cancers) (Arnold and Papani- ER␣, which is positively correlated with high CCND1 kolaou 2005). CCND1 oncogenic activity in the mam- expression levels as well as with the expression of a sig- nature set of transcription factors, including FoxA1, GATA3, and XBP-1 (for reviews, see Lacroix and 1Corresponding author. E-MAIL myles_brown@dfci.harvard.edu; FAX (617) 632-5417. Leclercq 2004; Lacroix et al. 2004; Arnold and Papani- Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1446006. kolaou 2005). Amplification of the CCND1 gene is pre- GENES & DEVELOPMENT 20:2513–2526 © 2006 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/06; www.genesdev.org 2513 Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Eeckhoute et al. sent only in a minority of CCND1-overexpressing breast through this enhancer to regulate CCND1 expression in cancers, indicating that pathogenic transcriptional acti- BCC. vation of this gene by factors such as ER␣ could be an important mechanism triggering its overexpression. Results Moreover, it has been shown that artificial induction of Identification of two DNase I-hypersensitive (HS) sites CCND1 mRNA expression in breast cancer cells (BCC) in the vicinity of the CCND1 gene that correspond mimics estrogen effects and is sufficient to drive S-phase to novel transcriptional enhancers entry (Prall et al. 1998) but is also able to reverse the growth-inhibitory effect of antiestrogens (Wilcken et al. Although previous work defining CCND1 gene regula- 1997). Accordingly, another study showed that the major tory regions focused primarily on the proximal 1-kb pro- antiproliferative effect of the antiestrogen tamoxifen moter (cited above and Fukami-Kobayashi and Mitsui could be related to its inhibition of CCND1 expression 1998; Eto 2000), analysis of sequence conservation across (Hodges et al. 2003). CCND1 silencing experiments in BCC further confirmed the correlation between CCND1 expression levels and cellular proliferation, emphasizing CCND1 as a potential therapeutic target for breast can- cer (Arnold and Papanikolaou 2005; Grillo et al. 2006). The mechanisms by which estrogen regulates CCND1 levels in BCC are primarily transcriptional. Transient transfection-based studies have mapped several potential estrogen-responsive sites in the CCND1 proximal pro- moter, including an atypical cyclic AMP response ele- ment (position −57), an AP1 site (position −954), and GC- rich sites (positions −110 and −143) (Altucci et al. 1996; Sabbah et al. 1999; Castro-Rivera et al. 2001; Liu et al. 2002; Park et al. 2005). Stable integration of reporter con- structs in BCC was recently used by Cicatiello et al. (2004) to show that in this context estrogen stimulation required primarily the AP1 site. These authors proposed that ER␣ loading at the CCND1 promoter upon estrogen stimulation was mediated through interaction with AP1, resulting in the assembly of an activator complex re- sponsible for CCND1 transcriptional induction. While these studies suggested the presence of poten- tial cis-regulatory elements involved in CCND1 expres- sion, none explain the cell-type-specific regulation of CCND1 by ER␣ (Planas-Silva et al. 1999). Here, we de- scribe the characterization of a novel estrogen-regulated cell-type-specific enhancer for CCND1 and the combi- natorial transcription factor network that functions Figure 1. Profiling of the DNase I sensitivity of the evolution- arily conserved regions in the vicinity of the CCND1 gene. (A) Schematic representation of the conserved regions at the CCND1 locus from the University of California at Santa Cruz genome browser. The CCND1 gene is shown at the top with blocks representing the exons. The track at the bottom of the gene shows a measure of evolutionary conservation between 17 vertebrate species based on a phylogenetic hidden Markov model. The conserved regions studied in this work upstream (−3000 to 0 bp; red frame) and downstream (d280–d880 bp; green frame) from the CCND1 gene are highlighted. The location of real-time PCR amplicons generated by PCR primer sets used throughout this work is indicated at the bottom part of the panel. (B–F) DNase I sensitivity assays were performed as indi- cated in Materials and Methods with intact nuclei from the indicated cells. The percent (%) of remaining DNA after partial digestion is indicated for every analyzed sequence throughout the CCND1 locus. Results are means ± SE from two indepen- dent experiments. The HS sites are indicated by the arrows at the bottom of the graphs and by the vertical dotted lines. 2514 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press CCND1 regulation by estrogen species indicated that additional regions ∼2and3kbup- DNAse I sensitive, but the difference in sensitivity with stream of the transcription start site were extremely well the neighboring sites was not as pronounced as in the conserved (Fig. 1A, red frame). Moreover, a potential human cell lines (Fig. 1F). The HS site at −50 bp is lo- ER␣-binding site was found downstream from the cated near the transcription start site, which contains CCND1 gene by an unbiased approach combining chro- known CRE- and Sp1-binding sites that are conserved matin immunoprecipitation (ChIP) and analysis of between human and mouse genomes (Eto 2000). In con- bound DNA by tiled microarrays covering the nonrepeti- trast, the HS sites at −2000 and d500 bp revealed new tive sequences of the whole genome (J.S. Carroll, C.A. potentially important regulatory regions. Meyer, J. Song,
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