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MTA Family of Transcriptional Metaregulators in Mammary Gland Morphogenesis and Breast Cancer

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Since breast cancer and its associated metastasis are a global health problem and a major cause of mortality among women, research efforts to understand the development, morphogenesis, and functioning of the mammary gland are a high priority. Myriad signaling pathways, transcription factors, and associated transcriptional coregulators have been identified in both normal functioning and neoplastic transformation of the mammary gland. The discovery of the metastasis tumor antigen 1 (MTA1) gene, its overexpression in cancer and metastasis and its subsequent identification as an integral part of the chromatin remodeling complex heralded extensive research on its physiological role. Subsequent identification of additional gene family members, namely MTA1s, MTA2, and MTA3, and their functions in the cell has resulted in the establishment of the significance of the MTA family. The role of these proteins in modulating hormonal responses in normal mammary glands and in breast cancer has resulted in their identification as important molecular markers and potential therapeutic targets.

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Abbreviations

MTA1:

metastasis tumor antigen 1

MTA1s:

MTA1 short form

NuRD complex:

nucleosome remodeling and deacetylase complex

ERα:

estrogen receptor α

PR:

progesterone receptor

HDAC:

histone deacetylase

ChIP:

chromatin immunoprecipitation

NR:

nuclear receptor

References

  1. Daniel CW, Silberstein GB, Strickland P. Direct action of 17 beta-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. Cancer Res 1987;47 22:6052–7.

    PubMed  CAS  Google Scholar 

  2. Imagawa W, Bandyopadhyay GK, Nandi S. Regulation of mammary epithelial cell growth in mice and rats. Endocr Rev 1990;11 4:494–523.

    Article  PubMed  CAS  Google Scholar 

  3. Haslam SZ. Local versus systemically mediated effects of estrogen on normal mammary epithelial cell deoxyribonucleic acid synthesis. Endocrinology 1988;122 3:860–67.

    Article  PubMed  CAS  Google Scholar 

  4. Silberstein GB, Van Horn K, Shyamala G, Daniel CW. Essential role of endogenous estrogen in directly stimulating mammary growth demonstrated by implants containing pure antiestrogens. Endocrinology 1994;134 1:84–90.

    Article  PubMed  CAS  Google Scholar 

  5. Singh RR, Kumar R. Steroid hormone receptor signaling in tumorigenesis. J Cell Biochem 2005;96 3:490–505.

    Article  PubMed  CAS  Google Scholar 

  6. Korach KS, Couse JF, Curtis SW, Washburn TF, Lindzey J, Kimbro KS, et al. Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. Recent Prog Horm Res 1996;51:159–86.

    PubMed  CAS  Google Scholar 

  7. Bocchinfuso WP, Korach KS. Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J Mammary Gland Biol Neoplasia 1997;2 4:323–34.

    Article  PubMed  CAS  Google Scholar 

  8. Scully KM, Gleiberman AS, Lindzey J, Lubahn DB, Korach KS, Rosenfeld MG. Role of estrogen receptor-alpha in the anterior pituitary gland. Mol Endocrinol 1997;11 6:674–81.

    Article  PubMed  CAS  Google Scholar 

  9. Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, et al. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci USA 1998;95 26:15677–82.

    Article  PubMed  CAS  Google Scholar 

  10. Cunha GR, Young P, Hom YK, Cooke PS, Taylor JA, Lubahn DB. Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombinants. J Mammary Gland Biol Neoplasia 1997;2 4:393–402.

    Article  PubMed  CAS  Google Scholar 

  11. Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci USA 2006;103 7:2196–201.

    Article  PubMed  CAS  Google Scholar 

  12. Brisken C, Park S, Vass T, Lydon JP, O’Malley BW, Weinberg RA. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci USA 1998;95 9:5076–81.

    Article  PubMed  CAS  Google Scholar 

  13. Kumar R, Gururaj AE, Vadlamudi RK, Rayala SK. The clinical relevance of steroid hormone receptor corepressors. Clin Cancer Res 2005;11 8:2822–31.

    Article  PubMed  CAS  Google Scholar 

  14. Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma. Breast Cancer Res Treat 1993;25 2:165–74.

    Article  PubMed  CAS  Google Scholar 

  15. Toh Y, Pencil SD, Nicolson GL. A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J Biol Chem 1994;269 37:22958–63.

    PubMed  CAS  Google Scholar 

  16. Toh Y, Oki E, Oda S, Tokunaga E, Ohno S, Maehara Y, et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis. Int J Cancer 1997;74 4:459–63.

    Article  PubMed  CAS  Google Scholar 

  17. Toh Y, Kuwano H, Mori M, Nicolson GL, Sugimachi K. Overexpression of metastasis-associated MTA1 mRNA in invasive oesophageal carcinomas. Br J Cancer 1999;79 11–12:1723–6.

    Article  PubMed  CAS  Google Scholar 

  18. Xue Y, Wong J, Moreno GT, Young MK, Cote J, Wang W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell 1998;2 6:851–61.

    Article  PubMed  CAS  Google Scholar 

  19. Cui Q, Takiguchi S, Matsusue K, Toh Y, Yoshida MA. Assignment of the human metastasis-associated gene 1 (MTA1) to human chromosome band 14q32.3 by fluorescence in situ hybridization. Cytogenet Cell Genet 2001;93 1–2:139–40.

    Article  PubMed  CAS  Google Scholar 

  20. Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev 1999;13 15:1924–35.

    PubMed  CAS  Google Scholar 

  21. Futamura M, Nishimori H, Shiratsuchi T, Saji S, Nakamura Y, Tokino T. Molecular cloning, mapping, and characterization of a novel human gene, MTA1-L1, showing homology to a metastasis-associated gene, MTA1. J Hum Genet 1999;44 1:52–6.

    Article  PubMed  CAS  Google Scholar 

  22. Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade PA. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 2003;113 2:207–19.

    Article  PubMed  CAS  Google Scholar 

  23. Kumar R, Wang RA, Mazumdar A, Talukder AH, Mandal M, Yang Z, et al. A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm. Nature 2002;418 6898:654–7.

    Article  PubMed  CAS  Google Scholar 

  24. Zhang H, Stephens LC, Kumar R. Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer. Clin Cancer Res 2006;12 5:1479–86.

    Article  PubMed  CAS  Google Scholar 

  25. Mishra SK, Talukder AH, Gururaj AE, Yang Z, Singh RR, Mahoney MG, et al. Upstream determinants of estrogen receptor-alpha regulation of metastatic tumor antigen 3 pathway. J Biol Chem 2004;279 31:32709–15.

    Article  PubMed  CAS  Google Scholar 

  26. Fujita N, Kajita M, Taysavang P, Wade PA. Hormonal regulation of metastasis-associated protein 3 transcription in breast cancer cells. Mol Endocrinol 2004;18 12:2937–49.

    Article  PubMed  CAS  Google Scholar 

  27. Cui Y, Niu A, Pestell R, Kumar R, Curran EM, Liu Y, et al. Metastasis-associated protein 2 is a repressor of estrogen receptor alpha whose overexpression leads to estrogen-independent growth of human breast cancer cells. Mol Endocrinol 2006;20 9:2020–35.

    Article  PubMed  CAS  Google Scholar 

  28. Goodwin GH, Nicolas RH. The BAH domain, polybromo and the RSC chromatin remodelling complex. Gene 2001;268 1–2:1–7.

    Article  PubMed  CAS  Google Scholar 

  29. Aasland R, Stewart AF, Gibson T. The SANT domain: a putative DNA-binding domain in the SWI-SNF and ADA complexes, the transcriptional co-repressor N-CoR and TFIIIB. Trends Biochem Sci 1996;21 3:87–8.

    Article  PubMed  CAS  Google Scholar 

  30. Waksman G, Kumaran S, Lubman O. SH2 domains: role, structure and implications for molecular medicine. Expert Rev Mol Med 2004;6 3:1–18.

    Article  PubMed  Google Scholar 

  31. Mazumdar A, Wang RA, Mishra SK, Adam L, Bagheri-Yarmand R, Mandal M, et al. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol 2001;3 1:30–7.

    Article  PubMed  CAS  Google Scholar 

  32. Tang CK, Perez C, Grunt T, Waibel C, Cho C, Lupu R. Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells. Cancer Res 1996;56 14:3350–8.

    PubMed  CAS  Google Scholar 

  33. Singh RR, Barnes CJ, Talukder AH, Fuqua SA, Kumar R. Negative regulation of estrogen receptor alpha transactivation functions by LIM domain only 4 protein. Cancer Res 2005;65 22:10594–601.

    Article  PubMed  CAS  Google Scholar 

  34. Chang C, Norris JD, Gron H, Paige LA, Hamilton PT, Kenan DJ et al. Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors alpha and beta. Mol Cell Biol 1999;19 12:8226–39.

    PubMed  CAS  Google Scholar 

  35. Singh RR, Kaluarachchi K, Chen M, Rayala SK, Balasenthil S, Ma J et al. Solution structure and antiestrogenic activity of the unique C-terminal, NR-box motif-containing region of MTA1s. J Biol Chem 2006;281 35:25612–21.

    Article  PubMed  CAS  Google Scholar 

  36. Price JE, Sauder DN, Fidler IJ. Tumorigenicity and metastatic behavior in nude mice of two human squamous cell carcinoma lines that differ in production of the cytokine ETAF/IL-1. J Invest Dermatol 1988;91 3:258–62.

    Article  PubMed  CAS  Google Scholar 

  37. Nicolson GL, Nawa A, Toh Y, Taniguchi S, Nishimori K, Moustafa A. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin Exp Metastasis 2003;20 1:19–24.

    Article  PubMed  CAS  Google Scholar 

  38. Martin MD, Hilsenbeck SG, Mohsin SK, Hopp TA, Clark GM, Osborne CK, et al. Breast tumors that overexpress nuclear metastasis-associated 1 (MTA1) protein have high recurrence risks but enhanced responses to systemic therapies. Breast Cancer Res Treat 2006;95 1:7–12.

    Article  PubMed  CAS  Google Scholar 

  39. Sasaki H, Moriyama S, Nakashima Y, Kobayashi Y, Yukiue H, Kaji M, et al. Expression of the MTA1 mRNA in advanced lung cancer. Lung Cancer 2002;35 2:149–54.

    Article  PubMed  Google Scholar 

  40. Hofer MD, Kuefer R, Varambally S, Li H, Ma J, Shapiro GI, et al. The role of metastasis-associated protein 1 in prostate cancer progression. Cancer Res 2004;64 3:825–9.

    Article  PubMed  CAS  Google Scholar 

  41. Bagheri-Yarmand R, Talukder AH, Wang RA, Vadlamudi RK, Kumar R. Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis. Development 2004;131 14:3469–79.

    Article  PubMed  CAS  Google Scholar 

  42. Zhang XY, DeSalle LM, Patel JH, Capobianco AJ, Yu D, Thomas-Tikhonenko A, et al. Metastasis-associated protein 1 (MTA1) is an essential downstream effector of the c-MYC oncoprotein. Proc Natl Acad Sci USA 2005;102 39:13968–73.

    Article  PubMed  CAS  Google Scholar 

  43. Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene 1999;18 19:3004–16.

    Article  PubMed  CAS  Google Scholar 

  44. Yoo YG, Kong G, Lee MO. Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO J 2006;25 6:1231–41.

    Article  PubMed  CAS  Google Scholar 

  45. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3 10:721–32.

    Article  PubMed  CAS  Google Scholar 

  46. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 1999;59 22:5830–5.

    PubMed  CAS  Google Scholar 

  47. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, et al. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 2002;111 5:709–20.

    Article  PubMed  CAS  Google Scholar 

  48. Gururaj AE, Singh RR, Rayala SK, Holm C, den Hollander P, Zhang H, et al. MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc Natl Acad Sci USA 2006;103 17:6670–5.

    Article  PubMed  CAS  Google Scholar 

  49. Mishra SK, Mazumdar A, Vadlamudi RK, Li F, Wang RA, Yu W, et al. MICoA, a novel metastasis-associated protein 1 (MTA1) interacting protein coactivator, regulates estrogen receptor-alpha transactivation functions. J Biol Chem 2003;278 21:19209–19.

    Article  PubMed  CAS  Google Scholar 

  50. Talukder AH, Gururaj A, Mishra SK, Vadlamudi RK, Kumar R. Metastasis-associated protein 1 interacts with NRIF3, an estrogen-inducible nuclear receptor coregulator. Mol Cell Biol 2004;24 15:6581–91.

    Article  PubMed  CAS  Google Scholar 

  51. Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 2002;21 20:3241–6.

    Article  PubMed  CAS  Google Scholar 

  52. Zhang H, Singh RR, Talukder AH, Kumar R. Metastatic tumor antigen 3 is a direct corepressor of the Wnt4 pathway. Genes Dev 2006;20 21:2943–8.

    Article  PubMed  CAS  Google Scholar 

  53. Brisken C, Heineman A, Chavarria T, Elenbaas B, Tan J, Dey SK et al. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev 2000;14 6:650–4.

    PubMed  CAS  Google Scholar 

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Acknowledgements

We thank colleagues in the Kumar laboratory for helpful discussions. Work in the author’s laboratory is supported by NIH grants CA98823 and CA65746, and The Norman Brinkler Award for Research Excellence (to R.K.).

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  1. Molecular and Cellular Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    Rajesh R. Singh & Rakesh Kumar

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  1. Rajesh R. Singh
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  2. Rakesh Kumar
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Correspondence to Rakesh Kumar.

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Singh, R.R., Kumar, R. MTA Family of Transcriptional Metaregulators in Mammary Gland Morphogenesis and Breast Cancer. J Mammary Gland Biol Neoplasia 12, 115–125 (2007). https://doi.org/10.1007/s10911-007-9043-7

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