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Breast Cancer Research

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Open Access 01-08-2007 | Research article

Characterization of a negative transcriptional element in the BRCA1 promoter

Authors: Gwen MacDonald, Melissa Stramwasser, Christopher R Mueller

Published in: Breast Cancer Research | Issue 4/2007

Abstract

Introduction

Decreased transcription of the BRCA1 gene has previously been observed to occur in sporadic breast tumours, making elucidation of the mechanisms regulating the expression of this gene important for our understanding of the etiology of the disease.

Methods

Transcriptional elements involved in the regulation of the BRCA1 promoter were analysed by co-transfection experiments into the human MCF-7 and T-47D breast cancer cell lines.

Results

We have identified a repressor element, referred to as the UP site, within the proximal BRCA1 promoter whose inactivation results in increased promoter activity. An E2F recognition element, previously suggested to mediate repression via E2F-6, is adjacent to the UP site and its inactivation also leads to increased BRCA1 expression. These two elements appear to form a composite repressor element whose combined effect is additive. The UP element is composed of two sequences, one of which binds the ubiquitously expressed ets family transcription factor GABP alpha/beta. This site is distinct from a previously identified GABP alpha/beta site, the RIBS element, though the RIBS site appears to be necessary for derepression of the promoter via mutations in the UP site. Knockdown of GABP alpha using an shRNA vector confirms that this protein is important for the function of both the RIBS and UP sites.

Conclusion

The identification of a repressor element in the BRCA1 promoter brings a new level of complexity to the regulation of BRCA1 expression. The elements characterized here may play a normal role in the integration of a variety of signals, including two different growth related pathways, and it is possible that loss of the ability to derepress the BRCA1 promoter during critical periods may contribute to breast transformation.

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Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994, 266: 66-71. 10.1126/science.7545954.CrossRefPubMed

Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y, et al: BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994, 266: 120-122. 10.1126/science.7939630.CrossRefPubMed

Papa S, Seripa D, Merla G, Gravina C, Giai M, Sismondi P, Rinaldi M, Serra A, Saglio G, Fazio VM: Identification of a possible somatic BRCA1 mutation affecting translation efficiency in an early-onset sporadic breast cancer patient. J Natl Cancer Inst. 1998, 90: 1011-1012. 10.1093/jnci/90.13.1011.CrossRefPubMed

van der LM, Cleton-Jansen AM, van Eijk R, Morreau H, van Vliet M, Kuipers-Dijkshoorn N, Olah E, Cornelisse CJ, Devilee P: A sporadic breast tumour with a somatically acquired complex genomic rearrangement in BRCA1. Genes Chromosomes Cancer. 2000, 27: 295-302. 10.1002/(SICI)1098-2264(200003)27:3<295::AID-GCC10>3.0.CO;2-F.CrossRef

Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT: Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nature Genet. 1995, 9: 444-450. 10.1038/ng0495-444.CrossRefPubMed

Catteau A, Harris WH, Xu CF, Solomon E: Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Oncogene. 1999, 18: 1957-1965. 10.1038/sj.onc.1202509.CrossRefPubMed

Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002, 108: 171-182. 10.1016/S0092-8674(02)00615-3.CrossRefPubMed

Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A, Deng CX: Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet. 1999, 22: 37-43. 10.1038/8743.CrossRefPubMed

Taylor J, Lymboura M, Pace PE, A'hern RP, Desai AJ, Shousha S, Coombes RC, Ali S: An important role for BRCA1 in breast cancer progression is indicated by its loss in a large proportion of non-familial breast cancers. Int J Can. 1998, 79: 334-342. 10.1002/(SICI)1097-0215(19980821)79:4<334::AID-IJC5>3.0.CO;2-W.CrossRef

10.

Wilson CA, Ramos L, Villasenor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, et al: Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet. 1999, 21: 236-240. 10.1038/6029.CrossRefPubMed

11.

Jarvis EM, Kirk JA, Clarke CL: Loss of nuclear BRCA1 expression in breast cancers is associated with a highly proliferative tumour phenotype. Cancer Genetics Cytogenet. 1998, 101: 109-115. 10.1016/S0165-4608(97)00267-7.CrossRef

12.

Mueller CR, Roskelley CD: Regulation of BRCA1 expression and its relationship to sporadic breast cancer. Breast Cancer Res. 2002, 5: 45-52. 10.1186/bcr557.CrossRefPubMedPubMedCentral

13.

Brown MA, Xu CF, Nicolai H, Griffiths B, Chambers JA, Black D, Solomon E: The 5' end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21. Oncogene. 1996, 12: 2507-2513.PubMed

14.

Xu CF, Brown MA, Nicolai H, Chambers JA, Griffiths BL, Solomon E: Isolation and characterisation of the NBR2 gene which lies head to head with the human BRCA1 gene. Hum Mol Gen. 1997, 6: 1057-1062. 10.1093/hmg/6.7.1057.CrossRefPubMed

15.

Suen TC, Goss PE: Transcription of BRCA1 is dependent on the formation of a specific protein-DNA complex on the minimal BRCA1 Bi-directional promoter. J Biol Chem. 1999, 274: 31297-31304. 10.1074/jbc.274.44.31297.CrossRefPubMed

16.

Atlas E, Stramwasser M, Whiskin K, Mueller CR: GA-binding protein alpha/beta is a critical regulator of the BRCA1 promoter. Oncogene. 2000, 19: 1933-1940. 10.1038/sj.onc.1203516.CrossRefPubMed

17.

LaMarco K, Thompson CC, Byers BP, Walton EM, McKnight SL: Identification of Ets- and Notch-related subunits in GA binding protein. Science. 1991, 253: 789-792. 10.1126/science.1876836.CrossRefPubMed

18.

LaMarco K, McKnight SL: Purification of a set of cellular polypeptides that bind to the purine-rich cis-regulatory element of herpes simplex virus immediate early genes. Genes Dev. 1989, 3: 1372-1383. 10.1101/gad.3.9.1372.CrossRefPubMed

19.

Rosmarin AG, Resendes KK, Yang Z, McMillan JN, Fleming SL: GA-binding protein transcription factor: a review of GABP as an integrator of intracellular signaling and protein-protein interactions. Blood Cells Mol Dis. 2004, 32: 143-154. 10.1016/j.bcmd.2003.09.005.CrossRefPubMed

20.

Fromm L, Burden SJ: Synapse-specific and neuregulin-induced transcription require an ets site that binds GABP alpha/GABP beta. Genes Dev. 1998, 12: 3074-3083.CrossRefPubMedPubMedCentral

21.

Siebenlist U, Gilbert W: Contacts between Escherichia coli RNA polymerase and an early promoter of phage T7. Proc Natl Acad Sci USA. 1980, 77: 122-126. 10.1073/pnas.77.1.122.CrossRefPubMedPubMedCentral

22.

Brummelkamp TR, Bernards R, Agami R: A system for stable expression of short interfering RNAs in mammalian cells. Science. 2002, 296: 550-553. 10.1126/science.1068999.CrossRefPubMed

23.

Rosmarin AG, Caprio DG, Kirsch DG, Handa H, Simkevich CP: GABP and PU.1 compete for binding, yet cooperate to increase CD18 (beta 2 leukocyte integrin) transcription. J Biol Chem. 1995, 270: 23627-23633. 10.1074/jbc.270.40.23627.CrossRefPubMed

24.

Oberley MJ, Inman DR, Farnham PJ: E2F6 negatively regulates BRCA1 in human cancer cells without methylation of histone H3 on lysine 9. J Biol Chem. 2003, 278: 42466-42476. 10.1074/jbc.M307733200.CrossRefPubMed

25.

Sawa C, Goto M, Suzuki F, Watanabe H, Sawada J, Handa H: Functional domains of transcription factor hGABP beta1/E4TF1–53 required for nuclear localization and transcription activation. Nucleic Acids Res. 1996, 24: 4954-4961. 10.1093/nar/24.24.4954.CrossRefPubMedPubMedCentral

26.

Wang A, Schneider-Broussard R, Kumar AP, MacLeod MC, Johnson DG: Regulation of BRCA1 expression by the Rb-E2F pathway. J Biol Chem. 2000, 275: 4532-4536. 10.1074/jbc.275.6.4532.CrossRefPubMed

27.

Bindra RS, Glazer PM: Basal repression of BRCA1 by multiple E2Fs and pocket proteins at adjacent E2F sites. Cancer Biol Ther. 2006, 5: 1400-1407.CrossRefPubMed

28.

Genuario RR, Perry RP: The GA-binding protein can serve as both an activator and repressor of ribosomal protein gene transcription. J Biol Chem. 1996, 271: 4388-4395. 10.1074/jbc.271.8.4388.CrossRefPubMed

29.

Suzuki F, Goto M, Sawa C, Ito S, Watanabe H, Sawada J, Handa H: Functional interactions of transcription factor human GA-binding protein subunits. J Biol Chem. 1998, 273: 29302-29308. 10.1074/jbc.273.45.29302.CrossRefPubMed

30.

Rauch T, Zhong X, Pfeifer GP, Xu X: 53BP1 is a positive regulator of the BRCA1 promoter. Cell Cycle. 2005, 4: 1078-1083.CrossRefPubMed

31.

Mochan TA, Venere M, DiTullio RA, Halazonetis TD: 53BP1, an activator of ATM in response to DNA damage. DNA Repair (Amst). 2004, 3: 945-952. 10.1016/j.dnarep.2004.03.017.CrossRef

32.

Gudas JM, Li T, Nguyen H, Jensen D, Rauscher FJ, Cowan KH: Cell cycle regulation of BRCA1 messenger RNA in human breast epithelial cells. Cell Growth Differ. 1996, 7: 717-723.PubMed

33.

Imaki H, Nakayama K, Delehouzee S, Handa H, Kitagawa M, Kamura T, Nakayama KI: Cell cycle-dependent regulation of the Skp2 promoter by GA-binding protein. Cancer Res. 2003, 63: 4607-4613.PubMed

34.

Yang ZF, Mott S, Rosmarin AG: The Ets transcription factor GABP is required for cell-cycle progression. Nat Cell Biol. 2007, 9: 339-346. 10.1038/ncb1548.CrossRefPubMed

35.

Suen TC, Tang MS, Goss PE: Model of transcriptional regulation of the BRCA1-NBR2 bi-directional transcriptional unit. Biochim Biophys Acta. 2005, 1728: 126-134.CrossRefPubMed

Title: Characterization of a negative transcriptional element in the BRCA1 promoter
Authors: Gwen MacDonald
Melissa Stramwasser
Christopher R Mueller
Publication date: 01-08-2007
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 4/2007
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/bcr1753

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Abstract

Introduction

Methods

Results

Conclusion

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