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Stem Cells and Cancer Stem Cells, Volume 6 pp 385–395Cite as

Inhibition of Breast Tumor Stem Cells Expansion by the Endogenous Cell Fate Determination Factor Dachshund

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Part of the book series: Stem Cells and Cancer Stem Cells ((STEM,volume 6))

Abstract

The Dachshund homolog 1 (Dach1) gene encodes a conserved co-repressor protein that, through its interaction with other nuclear proteins in the context of the local chromatin, participates in the regulation of genes essential for precursor cell proliferation and survival. DACH1 has been implicated in breast, prostate, ovarian and endometrial tumorigenesis. In breast cancer, reduced expression of DACH1 correlates with poor prognosis. Analysis of the mechanisms involved discovered that DACH1 binds and represses a subset of genes with important functions in tumorigenesis and tumor progression. By inhibiting chemokine expression, DACH1 reduces cellular migration, invasion, and metastatic capability of breast cancer cells. DACH1 also represses several AP-1-responsive genes, including the cell cycle regulator Cyclin D1. Recent studies demonstrated that endogenous DACH1 targets key regulators of stem cell identity in breast cancer cells. The present chapter summarizes the evidence that DACH1 regulates breast tumor progression and cancer stem cell expansion. We discuss the mechanisms involved.

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References

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988

    Article  PubMed  CAS  Google Scholar 

  • Backman M, Machon O, Van Den Bout CJ, Krauss S (2003) Targeted disruption of mouse Dach1 results in postnatal lethality. Dev Dyn 226:139–144

    Article  PubMed  CAS  Google Scholar 

  • Chen R, Amoui M, Zhang Z, Mardon G (1997) Dachshund and eyes absent proteins form a complex and function synergistically to induce ectopic eye development in Drosophila. Cell 91:893–903

    Article  PubMed  CAS  Google Scholar 

  • Curtiss J, Burnett M, Mlodzik M (2007) Distal antenna and distal antenna-related function in the retinal determination network during eye development in Drosophila. Dev Biol 306:685–702

    Article  PubMed  CAS  Google Scholar 

  • Davis RJ, Shen W, Sandler YI, Amoui M, Purcell P, Maas R, Ou CN, Vogel H, Beaudet AL, Mardon G (2001) Dach1 mutant mice bear no gross abnormalities in eye, limb, and brain development and exhibit postnatal lethality. Mol Cell Biol 21:1484–1490

    Article  PubMed  CAS  Google Scholar 

  • Davis RJ, Pesah YI, Harding M, Paylor R, Mardon G (2006) Mouse Dach2 mutants do not exhibit gross defects in eye development or brain function. Genesis 44:84–92

    Article  PubMed  CAS  Google Scholar 

  • Davis RJ, Harding M, Moayedi Y, Mardon G (2008) Mouse Dach1 and Dach2 are redundantly required for Mullerian duct development. Genesis 46:205–213

    Article  PubMed  CAS  Google Scholar 

  • De Larco JE, Wuertz BR, Yee D, Rickert BL, Furcht LT (2003) Atypical methylation of the interleukin-8 gene correlates strongly with the metastatic potential of breast carcinoma cells. Proc Natl Acad Sci USA 100:13988–13993

    Article  PubMed  Google Scholar 

  • Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10:R25

    Article  PubMed  Google Scholar 

  • Heberlein U, Treisman JE (2000) Early retinal development in Drosophila. Results Probl Cell Differ 31:37–50

    PubMed  CAS  Google Scholar 

  • Iliopoulos D, Hirsch HA, Wang G, Struhl K (2011) Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA 108:1397–1402

    Article  PubMed  CAS  Google Scholar 

  • Jiao X, Katiyar S, Willmarth NE, Liu M, Ma X, Flomenberg N, Lisanti MP, Pestell RG (2010) c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion. J Biol Chem 285:8218–8226

    Article  PubMed  CAS  Google Scholar 

  • Kim SS, Zhang RG, Braunstein SE, Joachimiak A, Cvekl A, Hegde RS (2002) Structure of the retinal determination protein Dachshund reveals a DNA binding motif. Structure 10:787–795

    Article  PubMed  CAS  Google Scholar 

  • Li X, Oghi KA, Zhang J, Krones A, Bush KT, Glass CK, Nigam SK, Aggarwal AK, Maas R, Rose DW, Rosenfeld MG (2003) Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426:247–254

    Article  PubMed  CAS  Google Scholar 

  • Liberati NT, Datto MB, Frederick JP, Shen X, Wong C, Rougier-Chapman EM, Wang XF (1999) Smads bind directly to the Jun family of AP-1 transcription factors. Proc Natl Acad Sci USA 96:4844–4849

    Article  PubMed  CAS  Google Scholar 

  • Lindsay J, Jiao X, Sakamaki T, Casimiro MC, Shirley LA, Tran TH, Ju X, Liu M, Li Z, Wang C, Katiyar S, Rao M, Allen KG, Glazer RI, Ge C, Stanley P, Lisanti MP, Rui H, Pestell RG (2008) ErbB2 induces Notch1 activity and function in breast cancer cells. Clin Transl Sci 1:107–115

    Article  PubMed  CAS  Google Scholar 

  • Ling H, Sylvestre JR, Jolicoeur P (2010) Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors. Oncogene 29:4543–4554

    Article  PubMed  CAS  Google Scholar 

  • Machon O, Backman M, Julin K, Krauss S (2000) Yeast two-hybrid system identifies the ubiquitin-conjugating enzyme mUbc9 as a potential partner of mouse Dac. Mech Dev 97:3–12

    Article  PubMed  CAS  Google Scholar 

  • Manavathi B, Kumar R (2006) Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin. J Cell Physiol 207:594–604

    Article  PubMed  CAS  Google Scholar 

  • Mardon G, Solomon NM, Rubin GM (1994) Dachshund encodes a nuclear protein required for normal eye and leg development in Drosophila. Development 120:3473–3486

    PubMed  CAS  Google Scholar 

  • McCoy EL, Iwanaga R, Jedlicka P, Abbey NS, Chodosh LA, Heichman KA, Welm AL, Ford HL (2009) Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. J Clin Invest 119:2663–2677

    Article  PubMed  CAS  Google Scholar 

  • Micalizzi DS, Christensen KL, Jedlicka P, Coletta RD, Baron AE, Harrell JC, Horwitz KB, Billheimer D, Heichman KA, Welm AL, Schiemann WP, Ford HL (2009) The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J Clin Invest 119:2678–2690

    Article  PubMed  CAS  Google Scholar 

  • Pappu KS, Mardon G (2004) Genetic control of retinal specification and determination in Drosophila. Int J Dev Biol 48:913–924

    Article  PubMed  Google Scholar 

  • Popov VM, Zhou J, Shirley LA, Quong J, Yeow WS, Wright JA, Wu K, Rui H, Vadlamudi RK, Jiang J, Kumar R, Wang C, Pestell RG (2009) The cell fate determination factor DACH1 is expressed in estrogen receptor-alpha-positive breast cancer and represses estrogen receptor-alpha signaling. Cancer Res 69:5752–5760

    Article  PubMed  CAS  Google Scholar 

  • Seimiya M, Gehring WJ (2000) The Drosophila homeobox gene optix is capable of inducing ectopic eyes by an eyeless-independent mechanism. Development 127:1879–1886

    PubMed  CAS  Google Scholar 

  • Shen W, Mardon G (1997) Ectopic eye development in Drosophila induced by directed dachshund expression. Development 124:45–52

    PubMed  CAS  Google Scholar 

  • Velasco-Velazquez MA, Li Z, Casimiro M, Loro E, Homsi N, Pestell RG (2011a) Examining the role of cyclin D1 in breast cancer. Future Oncol 7:753–765

    Article  PubMed  Google Scholar 

  • Velasco-Velazquez MA, Popov VM, Lisanti MP, Pestell RG (2011b) The role of breast cancer stem cells in metastasis and therapeutic implications. Am J Pathol 179:2–11

    Article  PubMed  CAS  Google Scholar 

  • Watanabe A, Ogiwara H, Ehata S, Mukasa A, Ishikawa S, Maeda D, Ueki K, Ino Y, Todo T, Yamada Y, Fukayama M, Saito N, Miyazono K, Aburatani H (2011) Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells. Proc Natl Acad Sci USA 108:12384–12389

    Article  PubMed  CAS  Google Scholar 

  • Weiss C, Schneider S, Wagner EF, Zhang X, Seto E, Bohmann D (2003) JNK phosphorylation relieves HDAC3-dependent suppression of the transcriptional activity of c-Jun. EMBO J 22:3686–3695

    Article  PubMed  CAS  Google Scholar 

  • Wu K, Yang Y, Wang C, Davoli MA, D’Amico M, Li A, Cveklova K, Kozmik Z, Lisanti MP, Russell RG, Cvekl A, Pestell RG (2003) DACH1 inhibits transforming growth factor-beta signaling through binding Smad4. J Biol Chem 278:51673–51684

    Article  PubMed  CAS  Google Scholar 

  • Wu K, Li A, Rao M, Liu M, Dailey V, Yang Y, Di Vizio D, Wang C, Lisanti MP, Sauter G, Russell RG, Cvekl A, Pestell RG (2006) DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth. Mol Cell Biol 26:7116–7129

    Article  PubMed  CAS  Google Scholar 

  • Wu K, Liu M, Li A, Donninger H, Rao M, Jiao X, Lisanti MP, Cvekl A, Birrer M, Pestell RG (2007) Cell fate determination factor DACH1 inhibits c-Jun-induced contact-independent growth. Mol Biol Cell 18(3):755–767

    Article  PubMed  CAS  Google Scholar 

  • Wu K, Katiyar S, Li A, Liu M, Ju X, Popov VM, Jiao X, Lisanti MP, Casola A, Pestell RG (2008) Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8. Proc Natl Acad Sci USA 105:6924–6929

    Article  PubMed  CAS  Google Scholar 

  • Wu K, Katiyar S, Witkiewicz A, Li A, McCue P, Song L-N, Tian L, Jin M, Pestell RG (2009) The cell fate determination factor dachshund inhibits androgen receptor and prostate cancer cellular growth. Cancer Res 69(8):3347–3355

    Article  PubMed  CAS  Google Scholar 

  • Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol M, Wei Z, Li A, Zhao J, Pestell RG (2011) The cell fate determination factor dachshund reprograms breast cancer stem cell function. J Biol Chem 286:2132–2142

    Article  PubMed  CAS  Google Scholar 

  • Yu Y, Khan J, Khanna C, Helman L, Meltzer PS, Merlino G (2004) Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med 10:175–181

    Article  PubMed  CAS  Google Scholar 

  • Yu Y, Davicioni E, Triche TJ, Merlino G (2006) The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res 66:1982–1989

    Article  PubMed  CAS  Google Scholar 

  • Zhou J, Liu Y, Zhang W, Popov VM, Wang M, Pattabiraman N, Sune C, Cvekl A, Wu K, Jiang J, Wang C, Pestell RG (2010a) Transcription elongation regulator 1 is a co-integrator of the cell fate determination factor Dachshund homolog 1. J Biol Chem 285:40342–40350

    Article  PubMed  CAS  Google Scholar 

  • Zhou J, Wang C, Wang Z, Dampier W, Wu K, Casimiro MC, Chepelev I, Popov VM, Quong A, Tozeren A, Zhao K, Lisanti MP, Pestell RG (2010b) Attenuation of Forkhead signaling by the retinal determination factor DACH1. Proc Natl Acad Sci USA 107:6864–6869

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by following NIH grants R01CA070896, R01CA075503, R01CA107382, R01CA132115, and R01CA086072 (R.G.P.). The Kimmel Cancer Center was supported by the NIH Cancer Center Core Grant P30CA56036 (to R.G.P.). This project is funded in part from the Marian C. Falk Medical Research Trust and a grant from the Pennsylvania Department of Health (R.G.P.). This project was also supported in part by Margaret Q. Landenberger Research Foundation (K. Wu) and National Natural Science Foundation of China No.81072169 (K. Wu).

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Authors and Affiliations

  1. Department of Cancer Biology, Thomas Jefferson University, 233 S. 10th Street, Philadelphia, PA, 19107, USA

    Marco Velasco-Velázquez, Kongming Wu, Emanuele Loro & Richard Pestell

  2. Pharmacology Department, School of Medicine, UNAM, Mexico, 04510, Mexico

    Marco Velasco-Velázquez

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  1. Marco Velasco-Velázquez
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  2. Kongming Wu
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  3. Emanuele Loro
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  4. Richard Pestell
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Correspondence to Kongming Wu or Richard Pestell .

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  1. , Kean University, Room 213, Library building, Morris Avenue 1000, Union, 07083, New Jersey, USA

    M.A. Hayat

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Velasco-Velázquez, M., Wu, K., Loro, E., Pestell, R. (2012). Inhibition of Breast Tumor Stem Cells Expansion by the Endogenous Cell Fate Determination Factor Dachshund. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 6. Stem Cells and Cancer Stem Cells, vol 6. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2993-3_34

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