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Comparative gene expression analysis in mouse models for identifying critical pathways in mammary gland development

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Abstract

Functional development of the mammary gland is an important physiological process. Several studies have used gene expression profiling of mammary gland development to identify the key genes in the process, but few focused on the involved pathways. And there is a lack of concordance between those observed pathways. In this article, we applied a standardized microarray preprocessing to four independent studies, and then used gene set enrichment analysis (GSEA) to identify the key pathways. The result demonstrated an increased concordance between these expression profiling data sets. From the stage of puberty to pregnancy, we found 7 up-regulated and 6 down-regulated pathways in common. From the period of pregnancy to lactation, we found 7 up-regulated and 58 down-regulated pathways in common. And 10 up-regulated and 3 down-regulated pathways were found in common from lactation to the involution period. The main canonical pathways identified belong to immune system, cell communication, metabolism, and disease-related pathways. Pathway analysis is a more effective method than single gene analysis because the former one can able to detect genes weakly connected to the phenotype. As we applied GSEA to the study, our findings suggested a greater concordance in this physiological process. The critical pathways we find can provide some insight of functional development of the mammary gland and motivate other relative studies.

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References

  1. Masso-Welch PA, Darcy KM, Stangle-Castor NC, Ip MM (2000) A developmental atlas of rat mammary gland histology. J Mammary Gland Biol Neoplasia 5:165–185

    Article  PubMed  CAS  Google Scholar 

  2. Richert MM, Schwertfeger KL, Ryder JW, Anderson SM (2000) An atlas of mouse mammary gland development. J Mammary Gland Biol Neoplasia 5:227–241

    Article  PubMed  CAS  Google Scholar 

  3. Rudolph MC, McManaman JL, Hunter L, Phang T, Neville MC (2003) Functional development of the mammary gland: use of expression profiling and trajectory clustering to reveal changes in gene expression during pregnancy, lactation, and involution. J Mammary Gland Biol Neoplasia 8:287–307

    Article  PubMed  Google Scholar 

  4. Clarkson RW, Wayland MT, Lee J, Freeman T, Watson CJ (2004) Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Res 6:R92–R109

    Article  PubMed  CAS  Google Scholar 

  5. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550

    Article  PubMed  CAS  Google Scholar 

  6. Visvader JE, Venter D, Hahm K, Santamaria M, Sum EY, O’Reilly L, White D, Williams R, Armes J, Lindeman GJ (2001) The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer. Proc Natl Acad Sci USA 98:14452–14457

    Article  PubMed  CAS  Google Scholar 

  7. Porter DA, Krop IE, Nasser S, Sgroi D, Kaelin CM, Marks JR, Riggins G, Polyak K (2001) A SAGE (serial analysis of gene expression) view of breast tumor progression. Cancer Res 61:5697–5702

    PubMed  CAS  Google Scholar 

  8. Stein T, Morris JS, Davies CR, Weber-Hall SJ, Duffy MA, Heath VJ, Bell AK, Ferrier RK, Sandilands GP, Gusterson BA (2004) Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res 6:R75–R91

    Article  PubMed  CAS  Google Scholar 

  9. Ron M, Israeli G, Seroussi E, Weller JI, Gregg JP, Shani M, Medrano JF (2007) Combining mouse mammary gland gene expression and comparative mapping for the identification of candidate genes for QTL of milk production traits in cattle. BMC Genomics 8:183

    Article  PubMed  Google Scholar 

  10. Anderson SM, Rudolph MC, McManaman JL, and Neville MC (2007) Key stages in mammary gland development. Secretory activation in the mammary gland: it’s not just about milk protein synthesis! Breast Cancer Res 9: 204

    Google Scholar 

  11. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273

    Article  PubMed  CAS  Google Scholar 

  12. Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5:R80

    Article  PubMed  Google Scholar 

  13. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264

    Article  PubMed  Google Scholar 

  14. Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) Affy-analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20:307–315

    Article  PubMed  CAS  Google Scholar 

  15. Gentleman R (2011). Using Categories to Analyze Microarray Data. http://www.bioconductor.org/packages/2.8/bioc/vignettes/Category/inst/doc/Category.pdf

  16. Manoli T, Gretz N, Grone HJ, Kenzelmann M, Eils R, Brors B (2006) Group testing for pathway analysis improves comparability of different microarray datasets. Bioinformatics 22:2500–2506

    Article  PubMed  CAS  Google Scholar 

  17. Robinson GW, Hennighausen L, Johnson PF (2000) Side-branching in the mammary gland: the progesterone-Wnt connection. Genes Dev 14:889–894

    PubMed  CAS  Google Scholar 

  18. Li M, Hu J, Heermeier K, Hennighausen L, Furth PA (1996) Expression of a viral oncoprotein during mammary gland development alters cell fate and function: induction of p53-independent apoptosis is followed by impaired milk protein production in surviving cells. Cell Growth Differ 7:3–11

    PubMed  CAS  Google Scholar 

  19. Singer KL, Stevenson BR, Woo PL, Firestone GL (1994) Relationship of serine/threonine phosphorylation/dephosphorylation signaling to glucocorticoid regulation of tight junction permeability and ZO-1 distribution in nontransformed mammary epithelial cells. J Biol Chem 269:16108–16115

    PubMed  CAS  Google Scholar 

  20. Buse P, Woo PL, Alexander DB, Reza A, Firestone GL (1995) Glucocorticoid-induced functional polarity of growth factor responsiveness regulates tight junction dynamics in transformed mammary epithelial tumor cells. J Biol Chem 270:28223–28227

    Article  PubMed  CAS  Google Scholar 

  21. Nguyen D-AD, Neville MC (1998) Tight junction regulation in the mammary gland. J Mammary Gland Biol Neoplasia 3:233–246

    Article  PubMed  CAS  Google Scholar 

  22. Mellenberger RW, Bauman DE (1974) Metabolic adaptations during lactogenesis fatty acid synthesis in rabbit mammary tissue during pregnancy and lactation. Biochem J 138:373–379

    PubMed  CAS  Google Scholar 

  23. Barcellos-Hoff MH, Derynck R, Tsang ML, Weatherbee JA (1994) Transforming growth factor-beta activation in irradiated murine mammary gland. J Clin Invest 93:892–899

    Article  PubMed  CAS  Google Scholar 

  24. Soriano JV, Pepper MS, Orci L, Montesano R (1998) Roles of hepatocyte growth factor/scatter factor and transforming growth factor-β1 in mammary gland ductal morphogenesis. J Mammary Gland Biol Neoplasia 3:133–150

    Article  PubMed  CAS  Google Scholar 

  25. Wakefield LM, Piek E, Bottinger EP (2001) TGF-beta signaling in mammary gland development and tumorigenesis. J Mammary Gland Biol Neoplasia 6:67–82

    Article  PubMed  CAS  Google Scholar 

  26. Robinson SD, Silberstein GB, Roberts AB, Flanders KC, Daniel CW (1991) Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms in mouse mammary gland development. Development 113:867–878

    PubMed  CAS  Google Scholar 

  27. Sordillo LM, Shafer-Weaver K, DeRosa D (1997) Immunobiology of the mammary gland. J Dairy Sci 80:1851–1865

    Article  PubMed  CAS  Google Scholar 

  28. Weisz-Carrington P, Roux ME, McWilliams M, Phillips-Quagliata JM, Lamm ME (1978) Hormonal induction of the secretory immune system in the mammary gland. Proc Natl Acad Sci USA 75:2928–2932

    Article  PubMed  CAS  Google Scholar 

  29. Wiseman BS, Werb Z (2002) Stromal effects on mammary gland development and breast cancer. Science 296:1046–1049

    Article  PubMed  CAS  Google Scholar 

  30. Schorr K, Li M, Krajewski S, Reed JC, Furth PA (1999) Bcl-2 gene family and related proteins in mammary gland involution and breast cancer. J Mammary Gland Biol Neoplasia 4:153–164

    Article  PubMed  CAS  Google Scholar 

  31. Cao Y, Karin M (2003) NF-κB in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 8:215–223

    Article  PubMed  Google Scholar 

  32. Politi K, Feirt N, Kitajewski J (2004) Notch in mammary gland development and breast cancer. Semin Cancer Biol 14:341–347

    Article  PubMed  CAS  Google Scholar 

  33. Russo J, Hu YF, Silva ID, Russo IH (2001) Cancer risk related to mammary gland structure and development. Microsc Res Tech 52:204–223

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant nos. 30871782 and 30671492).

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Authors and Affiliations

  1. School of Agriculture and Biology, Shanghai Jiao Tong University, No. 800 of Dong Chuan Road, Shanghai, 200240, China

    Mini Huang, Qiang Chen, Qishan Wang & Yuchun Pan

  2. Institute of Molecular and Clinical Medicine, Kunming Medical College, No. 1168, West Chunrong Road, Yuhua Street, Chenggong New Town, Kunming, 650500, China

    Hongbo Zhao

  3. Shanghai Key Lab for Animal Bio-technology, No. 800 of Dong Chuan Road, Shanghai, 200240, China

    Qiang Chen, Qishan Wang & Yuchun Pan

Authors
  1. Hongbo Zhao
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  2. Mini Huang
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  3. Qiang Chen
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  5. Yuchun Pan
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Corresponding author

Correspondence to Yuchun Pan.

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Hongbo Zhao and Mini Huang contributed equally to this study.

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Zhao, H., Huang, M., Chen, Q. et al. Comparative gene expression analysis in mouse models for identifying critical pathways in mammary gland development. Breast Cancer Res Treat 132, 969–977 (2012). https://doi.org/10.1007/s10549-011-1650-8

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  • DOI: https://doi.org/10.1007/s10549-011-1650-8

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