Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation

Oncogene volume 31, pages 116–127 (2012)Cite this article

Abstract

Expression of the breast cancer-associated gene 1 (BRCA1) in sporadic breast cancers is usually reduced, yet the underlying mechanisms remains elusive. To identify factors that are responsible for reduced BRCA1 expression, we screened 92 known transcription factors for their ability to regulate expression of BRCA1. Among several potential regulators, the Gli-Krueppel-related transcription factor Yin Yang 1 (YY1) showed the most dramatic transactivation of the BRCA1 promoter. YY1 binds to the promoter of BRCA1, and its overexpression resulted in increased expression of BRCA1 and a number of BRCA1 downstream genes. We further showed that overexpression of YY1 in cancer cells inhibited cell proliferation, foci formation and tumor growth in nude mice. To assess the clinical relevance between YY1 and BRCA1, we studied expression of YY1 and BRCA1 from human breast cancer samples and tissue arrays, and detected a significant positive correlation between the level of YY1 and BRCA1 expression in these cancers. Taken together, these findings suggest that YY1 is a key regulator of BRCA1 expression and may be causally linked to the molecular etiology of human breast cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Affar el B, Gay F, Shi Y, Liu H, Huarte M, Wu S et al. (2006). Essential dosage-dependent functions of the transcription factor yin yang 1 in late embryonic development and cell cycle progression. Mol Cell Biol 26: 3565–3581.

    Article  Google Scholar 

  • Alberg AJ, Lam AP, Helzlsouer KJ . (1999). Epidemiology, prevention, and early detection of breast cancer. Curr Opin Oncol 11: 435–441.

    Article  CAS  Google Scholar 

  • Atlas E, Stramwasser M, Mueller CR . (2001). A CREB site in the BRCA1 proximal promoter acts as a constitutive transcriptional element. Oncogene 20: 7110–7114.

    Article  CAS  Google Scholar 

  • Atlas E, Stramwasser M, Whiskin K, Mueller CR . (2000). GA-binding protein alpha/beta is a critical regulator of the BRCA1 promoter. Oncogene 19: 1933–1940.

    Article  CAS  Google Scholar 

  • Austen M, Cerni C, Luscher-Firzlaff JM, Luscher B . (1998). YY1 can inhibit c-Myc function through a mechanism requiring DNA binding of YY1 but neither its transactivation domain nor direct interaction with c-Myc. Oncogene 17: 511–520.

    Article  CAS  Google Scholar 

  • Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, Trapasso F et al. (2003). Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma. Mol Cell Biol 23: 2225–2238.

    Article  Google Scholar 

  • Beger C, Pierce LN, Kruger M, Marcusson EG, Robbins JM, Welcsh P et al. (2001). Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. Proc Natl Acad Sci USA 98: 130–135.

    Article  CAS  Google Scholar 

  • Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE . (2006). Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 8: R38.

    Article  Google Scholar 

  • Brody LC, Biesecker BB . (1998). Breast cancer susceptibility genes. BRCA1 and BRCA2. Medicine (Baltimore) 77: 208–226.

    Article  CAS  Google Scholar 

  • Castellano G, Torrisi E, Ligresti G, Malaponte G, Militello L, Russo AE et al. (2009). The involvement of the transcription factor Yin Yang 1 in cancer development and progression. Cell Cycle 8: 1367–1372.

    Article  CAS  Google Scholar 

  • Deng CX . (2006). BRCA1: cell cycle checkpoint, genetic instability, DNA damage response, and cancer evolution. Nucleic Acids Res 34: 1416–1426.

    Article  CAS  Google Scholar 

  • Drost RM, Jonkers J . (2009). Preclinical mouse models for BRCA1-associated breast cancer. Br J Cancer 101: 1651–1657.

    Article  CAS  Google Scholar 

  • Eccles DM, Pichert G . (2005). Familial non-BRCA1/BRCA2-associated breast cancer. Lancet Oncol 6: 705–711.

    Article  CAS  Google Scholar 

  • Furlong EE, Rein T, Martin F . (1996). YY1 and NF1 both activate the human p53 promoter by alternatively binding to a composite element, and YY1 and E1A cooperate to amplify p53 promoter activity. Mol Cell Biol 16: 5933–5945.

    Article  CAS  Google Scholar 

  • Ghosh S, Lu Y, Hu Y . (2008). A role of CREB in BRCA1 constitutive promoter activity and aromatase basal expression. Int J Biomed Sci 4: 260–265.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Giacinti L, Vici P, Lopez M . (2008). Epigenome: a new target in cancer therapy. Clin Ter 159: 347–360.

    CAS  PubMed  Google Scholar 

  • Gilbert PM, Mouw JK, Unger MA, Lakins JN, Gbegnon MK, Clemmer VB et al. (2010). HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. J Clin Invest 120: 1535–1550.

    Article  CAS  Google Scholar 

  • Glait C, Ravid D, Lee SW, Liscovitch M, Werner H . (2006). Caveolin-1 controls BRCA1 gene expression and cellular localization in human breast cancer cells. FEBS Lett 580: 5268–5274.

    Article  CAS  Google Scholar 

  • Gordon S, Akopyan G, Garban H, Bonavida B . (2006). Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene 25: 1125–1142.

    Article  CAS  Google Scholar 

  • Gronroos E, Terentiev AA, Punga T, Ericsson J . (2004). YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc Natl Acad Sci USA 101: 12165–12170.

    Article  Google Scholar 

  • Jin Y, Xu XL, Yang MC, Wei F, Ayi TC, Bowcock AM et al. (1997). Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains. Proc Natl Acad Sci USA 94: 12075–12080.

    Article  CAS  Google Scholar 

  • Kluk BJ, Fu Y, Formolo TA, Zhang L, Hindle AK, Man YG et al. (2010). BP1, an isoform of DLX4 homeoprotein, negatively regulates BRCA1 in sporadic breast cancer. Int J Biol Sci 6: 513–524.

    Article  CAS  Google Scholar 

  • Lee JS, Galvin KM, See RH, Eckner R, Livingston D, Moran E et al. (1995a). Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300. Genes Dev 9: 1188–1198.

    Article  CAS  Google Scholar 

  • Lee JS, See RH, Galvin KM, Wang J, Shi Y . (1995b). Functional interactions between YY1 and adenovirus E1A. Nucleic Acids Res 23: 925–931.

    Article  CAS  Google Scholar 

  • Lee MH, Kim YJ, Yoon WJ, Kim JI, Kim BG, Hwang YS et al. (2005). Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter. J Biol Chem 280: 35579–35587.

    Article  CAS  Google Scholar 

  • MacDonald G, Stramwasser M, Mueller CR . (2007). Characterization of a negative transcriptional element in the BRCA1 promoter. Breast Cancer Res 9: R49.

    Article  Google Scholar 

  • Man YG, Fu SW, Schwartz A, Pinzone JJ, Simmens SJ, Berg PE . (2005). Expression of BP1, a novel homeobox gene, correlates with breast cancer progression and invasion. Breast Cancer Res Treat 90: 241–247.

    Article  CAS  Google Scholar 

  • Oliveira AM, Ross JS, Fletcher JA . (2005). Tumor suppressor genes in breast cancer: the gatekeepers and the caretakers. Am J Clin Pathol 124 (Suppl): S16–S28.

    CAS  PubMed  Google Scholar 

  • Okada S, Ouchi T . (2003). Cell cycle differences in DNA damage-induced BRCA1 phosphorylation affect its subcellular localization. J Biol Chem 278: 2015–2020.

    Article  CAS  Google Scholar 

  • Park K, Atchison ML . (1991). Isolation of a candidate repressor/activator, NF-E1 (YY-1, delta), that binds to the immunoglobulin kappa 3′ enhancer and the immunoglobulin heavy-chain mu E1 site. Proc Natl Acad Sci USA 88: 9804–9808.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Riggs KJ, Saleque S, Wong KK, Merrell KT, Lee JS, Shi Y et al. (1993). Yin-yang 1 activates the c-myc promoter. Mol Cell Biol 13: 7487–7495.

    Article  CAS  Google Scholar 

  • Rivenbark AG, Coleman WB . (2009). Epigenetic regulation of cystatins in cancer. Front Biosci 14: 453–462.

    Article  Google Scholar 

  • Ruffner H, Verma IM . (1997). BRCA1 is a cell cycle-regulated nuclear phosphoprotein. Proc Natl Acad Sci USA 94: 7138–7143.

    Article  CAS  Google Scholar 

  • Shi Y, Lee JS, Galvin KM . (1997). Everything you have ever wanted to know about Yin Yang 1. Biochim Biophys Acta 1332: F49–F66.

    CAS  Google Scholar 

  • Shi Y, Seto E, Chang LS, Shenk T . (1991). Transcriptional repression by YY1, a human GLI-Kruppel-related protein, and relief of repression by adenovirus E1A protein. Cell 67: 377–388.

    Article  CAS  Google Scholar 

  • Suen TC, Goss PE . (2001). Identification of a novel transcriptional repressor element located in the first intron of the human BRCA1 gene. Oncogene 20: 440–450.

    Article  CAS  Google Scholar 

  • Sui G, Affar el B, Shi Y, Brignone C, Wall NR, Yin P et al. (2004). Yin Yang 1 is a negative regulator of p53. Cell 117: 859–872.

    Article  CAS  Google Scholar 

  • Tan SH, Baker CC, Stunkel W, Bernard HU . (2003). A transcriptional initiator overlaps with a conserved YY1 binding site in the long control region of human papillomavirus type 16. Virology 305: 486–501.

    Article  CAS  Google Scholar 

  • Thakur S, Croce CM . (1999). Positive regulation of the BRCA1 promoter. J Biol Chem 274: 8837–8843.

    Article  CAS  Google Scholar 

  • Turner JM, Aprelikova O, Xu X, Wang R, Kim S, Chandramouli GV et al. (2004a). BRCA1, histone H2AX phosphorylation, and male meiotic sex chromosome inactivation. Curr Biol 14: 2135–2142.

    Article  CAS  Google Scholar 

  • Turner N, Tutt A, Ashworth A . (2004b). Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4: 814–819.

    Article  CAS  Google Scholar 

  • Wang A, Schneider-Broussard R, Kumar AP, MacLeod MC, Johnson DG . (2000). Regulation of BRCA1 expression by the Rb-E2F pathway. J Biol Chem 275: 4532–4536.

    Article  CAS  Google Scholar 

  • Wang CC, Tsai MF, Dai TH, Hong TM, Chan WK, Chen JJ et al. (2007). Synergistic activation of the tumor suppressor, HLJ1, by the transcription factors YY1 and activator protein 1. Cancer Res 67: 4816–4826.

    Article  CAS  Google Scholar 

  • Wang CC, Tsai MF, Hong TM, Chang GC, Chen CY, Yang WM et al. (2005). The transcriptional factor YY1 upregulates the novel invasion suppressor HLJ1 expression and inhibits cancer cell invasion. Oncogene 24: 4081–4093.

    Article  CAS  Google Scholar 

  • Wang RH, Yu H, Deng CX . (2004). A requirement for breast-cancer-associated gene 1 (BRCA1) in the spindle checkpoint. Proc Natl Acad Sci USA 101: 17108–17113.

    Article  CAS  Google Scholar 

  • Wu S, Hu YC, Liu H, Shi Y . (2009). Loss of YY1 impacts the heterochromatic state and meiotic double-strand breaks during mouse spermatogenesis. Mol Cell Biol 29: 6245–6256.

    Article  CAS  Google Scholar 

  • Wu S, Murai S, Kataoka K, Miyagishi M . (2007a). Cooperative regulation of p73 promoter by Yin Yang 1 and E2F1. Nucleic Acids Symp Ser (Oxf) 51: 347–348.

    Article  Google Scholar 

  • Wu S, Shi Y, Mulligan P, Gay F, Landry J, Liu H et al. (2007b). A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair. Nat Struct Mol Biol 14: 1165–1172.

    Article  CAS  Google Scholar 

  • Wu W, Sato K, Koike A, Nishikawa H, Koizumi H, Venkitaraman AR et al. (2010). HERC2 is an E3 ligase that targets BRCA1 for degradation. Cancer Res 70: 6384–6392.

    Article  CAS  Google Scholar 

  • Xu CF, Brown MA, Nicolai H, Chambers JA, Griffiths BL, Solomon E . (1997a). Isolation and characterisation of the NBR2 gene which lies head to head with the human BRCA1 gene. Hum Mol Genet 6: 1057–1062.

    Article  CAS  Google Scholar 

  • Xu CF, Chambers JA, Solomon E . (1997b). Complex regulation of the BRCA1 gene. J Biol Chem 272: 20994–20997.

    Article  CAS  Google Scholar 

  • Xu X, Aprelikova O, Moens P, Deng CX, Furth PA . (2003). Impaired meiotic DNA-damage repair and lack of crossing-over during spermatogenesis in BRCA1 full-length isoform deficient mice. Development 130: 2001–2012.

    Article  CAS  Google Scholar 

  • Zhang J, Powell SN . (2005). The role of the BRCA1 tumor suppressor in DNA double-strand break repair. Mol Cancer Res 3: 531–539.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank members of Dr Deng laboratory for their critical discussion of this work and technical assistance. This research was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA.

Author information

Authors and Affiliations

  1. Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    M-H Lee, T Lahusen, R-H Wang, C Xiao, X Xu & C-X Deng

  2. Laboratory of Cell and Developmental Signaling, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA

    Y-S Hwang

  3. Origene Technologies, Inc., 9620 Medical Center Dr, Rockville, MD, USA

    W-W He

  4. Department of Pathology, Harvard Medical School, Boston, MA, USA

    Y Shi

Authors
  1. M-H Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Lahusen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R-H Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. X Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y-S Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W-W He
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C-X Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C-X Deng.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, MH., Lahusen, T., Wang, RH. et al. Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. Oncogene 31, 116–127 (2012). https://doi.org/10.1038/onc.2011.217

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.217

Keywords

This article is cited by

Search

Advanced search

Quick links