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:

hPMC2 is required for recruiting an ERβ coactivator complex to mediate transcriptional upregulation of NQO1 and protection against oxidative DNA damage by tamoxifen

Oncogene volume 27, pages 6376–6384 (2008)Cite this article

Abstract

In the presence of ERβ, trans-hydroxytamoxifen (TOT) protects cells against 17β-estradiol (E2)-induced oxidative DNA damage (ODD) and this correlates with increased expression of the antioxidative enzyme quinone reductase (QR). Here, we investigate the molecular mechanism responsible for ERβ-mediated protection against ODD. We observe constitutive interaction between ERβ and the novel protein hPMC2. Using a combination of breast epithelial cell lines that are either positive or negative for ERα, we demonstrate TOT-dependent recruitment of both ERβ and hPMC2 to the EpRE (electrophile response element)-regulated antioxidative enzyme QR. We further demonstrate TOT-dependent corecruitment of the coactivators Nrf2, PARP-1 (poly (ADP-ribose) polymerase 1) and topoisomerase IIβ, both in the presence and absence of ERα. However, absence of either ERβ or hPMC2 results in nonrecruitment of PARP-1 and topoisomerase IIβ, loss of antioxidative enzyme induction and attenuated protection against ODD by TOT even in the presence of Nrf2 and ERα. These findings indicate minor role for Nrf2 and ERα in TOT-dependent antioxidative gene regulation. However, downregulation of PARP-1 attenuates TOT-dependent antioxidative gene induction. We conclude that ERβ and hPMC2 are required for TOT-dependent recruitment of coactivators such as PARP-1 to the EpRE resulting in the induction of antioxidative enzymes and subsequent protection against ODD.

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

Similar content being viewed by others

References

  • Bianco NR, Perry G, Smith MA, Templeton DJ, Montano MM . (2003). Functional implications of antiestrogen induction of quinone reductase: inhibition of estrogen-induced DNA damage. Mol Endocrinol 17: 1344–1355.

    Article  CAS  PubMed  Google Scholar 

  • Bolton JL, Thatcher GR . (2008). Potential mechanisms of estrogen quinone carcinogenesis. Chem Res Toxicol 21: 93–101.

    Article  PubMed  Google Scholar 

  • Brummelkamp TR, Bernards R, Agami R . (2002). A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550–553.

    Article  CAS  PubMed  Google Scholar 

  • Cavalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R et al. (2006). Catechol estrogen quinones as initiators of breast and other human cancers: Implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta; e-pub ahead of print.

  • Chang EC, Frasor J, Komm B, Katzenellenbogen BS . (2006). Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology 147: 4831–4842.

    Article  CAS  PubMed  Google Scholar 

  • Fabian C . (2007). Tamoxifen or raloxifene in postmenopausal women for prevention of breast cancer: a tale of two choices--counterpoint. Cancer Epidemiol Biomarkers Prev 16: 2210–2212.

    Article  CAS  PubMed  Google Scholar 

  • Gaikwad NW, Rogan EG, Cavalieri EL . (2007). Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones. Free Rad Biol Med 43: 1289–1298.

    Article  CAS  PubMed  Google Scholar 

  • Gruvberger-Saal SK, Bendahl PO, Saal LH, Laakso M, Hegardt C, Eden P et al. (2007). Estrogen receptor beta expression is associated with tamoxifen response in ERalpha-negative breast carcinoma. Clin Cancer Res 13: 1987–1994.

    Article  CAS  PubMed  Google Scholar 

  • Jordan VC . (2007). Tamoxifen or raloxifene for breast cancer chemoprevention: a tale of two choices–point. Cancer Epidemiol Biomarkers Prev 16: 2207–2209.

    Article  CAS  PubMed  Google Scholar 

  • Ju BG, Lunyak VV, Perissi V, Garcia-Bassets I, Rose DW, Glass CK et al. (2006). A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science 312: 1798–1802.

    Article  CAS  PubMed  Google Scholar 

  • Krishnakumar R, Gamble MJ, Frizzell KM, Berrocal JG, Kininis M, Kraus WL . (2008). Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes. Science 319: 819–821.

    Article  CAS  PubMed  Google Scholar 

  • Li KM, Todorovic R, Devanesan P, Higginbotham S, Kofeler H, Ramanathan R et al. (2004). Metabolism and DNA binding studies of 4-hydroxyestradiol and estradiol-3,4-quinone in vitro and in female ACI rat mammary gland in vivo. Carcinogenesis 25: 289–297.

    Article  CAS  PubMed  Google Scholar 

  • Liehr JG . (2000). Is estradiol a genotoxic mutagenic carcinogen? Endocr Rev 21: 40–54.

    CAS  PubMed  Google Scholar 

  • Lis JT, Kraus WL . (2006). Promoter cleavage: a topoIIbeta and PARP-1 collaboration. Cell 125: 1225–1227.

    Article  CAS  PubMed  Google Scholar 

  • Matthews J, Gustafsson JA . (2003). Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol Interv 3: 281–292.

    Article  CAS  PubMed  Google Scholar 

  • Matthews J, Wihlen B, Tujague M, Wan J, Strom A, Gustafsson JA . (2006). Estrogen receptor (ER) beta modulates ERalpha-mediated transcriptional activation by altering the recruitment of c-Fos and c-Jun to estrogen-responsive promoters. Mol Endocrinol 20: 534–543.

    Article  CAS  PubMed  Google Scholar 

  • Menzel HJ, Sarmanova J, Soucek P, Berberich R, Grunewald K, Haun M et al. (2004). Association of NQO1 polymorphism with spontaneous breast cancer in two independent populations. Br J Cancer 90: 1989–1994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montano MM, Chaplin L, Deng H, Mesia-Vela S, Gaikwad N, Zahid M et al. (2007). Protective roles of quinone reductase and antiestrogens in estrogen-induced mammary cell tumorigenesis. Oncogene 26: 3587–3590.

    Article  CAS  PubMed  Google Scholar 

  • Montano MM, Deng H, Liu M, Sun X, Singal R . (2004). Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications. Oncogene 23: 2442–2453.

    Article  CAS  PubMed  Google Scholar 

  • Montano MM, Jaiswal AK, Katzenellenbogen BS . (1998). Transcriptional regulation of the human quinone reductase gene by antiestrogen-liganded estrogen receptor-alpha and estrogen receptor-beta. J Biol Chem 273: 25443–25449.

    Article  CAS  PubMed  Google Scholar 

  • Montano MM, Wittmann BM, Bianco NR . (2000). Identification and characterization of a novel factor that regulates quinone reductase gene transcriptional activity. J Biol Chem 275: 34306–34313.

    Article  CAS  PubMed  Google Scholar 

  • Oestergaard MZ, Tyrer J, Cebrian A, Shah M, Dunning AM, Ponder BA et al. (2006). Interactions between genes involved in the antioxidant defence system and breast cancer risk. Br J Cancer 95: 525–531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ et al. (1997). Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 277: 1508–1510.

    Article  CAS  PubMed  Google Scholar 

  • Pavri R, Lewis B, Kim TK, Dilworth FJ, Erdjument-Bromage H, Tempst P et al. (2005). PARP-1 determines specificity in a retinoid signaling pathway via direct modulation of mediator. Mol Cell 18: 83–96.

    Article  CAS  PubMed  Google Scholar 

  • Pettersson K, Grandien K, Kuiper GG, Gustafsson JA . (1997). Mouse estrogen receptor beta forms estrogen response element-binding heterodimers with estrogen receptor alpha. Mol Endocrinol 11: 1486–1496.

    CAS  PubMed  Google Scholar 

  • Prestera T, Talalay P . (1995). Electrophile and antioxidant regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci USA 92: 8965–8969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P et al. (2001). Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98: 3410–3415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Routledge EJ, White R, Parker MG, Sumpter JP . (2000). Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) alpha and ER beta. J Biol Chem 275: 35986–35993.

    Article  CAS  PubMed  Google Scholar 

  • Rushmore TH, Morton MR, Pickett CB . (1991). The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 266: 11632–11639.

    CAS  PubMed  Google Scholar 

  • Sakoda LC, Blackston CR, Xue K, Doherty JA, Ray RM, Lin MG et al. (2007). Glutathione S-transferase M1 and P1 polymorphisms and risk of breast cancer and fibrocystic breast conditions in Chinese women. Breast Cancer Res Treat.

  • Shang Y, Brown M . (2002). Molecular determinants for the tissue specificity of SERMs. Science 295: 2465–2468.

    Article  CAS  PubMed  Google Scholar 

  • Speirs V, Walker RA . (2007). New perspectives into the biological and clinical relevance of oestrogen receptors in the human breast. J Pathol 211: 499–506.

    Article  CAS  PubMed  Google Scholar 

  • Strange RC, Spiteri MA, Ramachandran S, Fryer AA . (2001). Glutathione-S-transferase family of enzymes. Mutat Res 482: 21–26.

    Article  CAS  PubMed  Google Scholar 

  • Tew KD . (1994). Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 54: 4313–4320.

    CAS  PubMed  Google Scholar 

  • Udler M, Maia AT, Cebrian A, Brown C, Greenberg D, Shah M et al. (2007). Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. J Clin Oncol 25: 3015–3023.

    Article  CAS  PubMed  Google Scholar 

  • Venugopal R, Jaiswal AK . (1996). Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci USA 93: 14960–14965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong CW, Komm B, Cheskis BJ . (2001). Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands. Biochemistry 40: 6756–6765.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH Grants (CA92440 and CA130066) to MMM.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA

    S P Sripathy, L J Chaplin & M M Montano

  2. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA

    N W Gaikwad & E G Rogan

Authors
  1. S P Sripathy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L J Chaplin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N W Gaikwad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E G Rogan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M M Montano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M M Montano.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sripathy, S., Chaplin, L., Gaikwad, N. et al. hPMC2 is required for recruiting an ERβ coactivator complex to mediate transcriptional upregulation of NQO1 and protection against oxidative DNA damage by tamoxifen. Oncogene 27, 6376–6384 (2008). https://doi.org/10.1038/onc.2008.235

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.235

Keywords

This article is cited by

Search

Advanced search

Quick links