Transcription Regulation Network Analysis of MCF7 Breast Cancer Cells Exposed to Estradiol

  • Wu, Jun-Zhao (Breast Cancer Diagnosis and Treatment Center, Henan Cancer Hospital) ;
  • Lu, Peng (Department of Oncological Surgery, People's Hospital of Zhengzhou) ;
  • Liu, Rong (Academician Experts Workstation of Henan Province, People's Hospital of Zhengzhou) ;
  • Yang, Tie-Jian (Department of Oncological Surgery, People's Hospital of Zhengzhou)
  • Published : 2012.08.31


Background: In breast cancer, estrogen receptors have been demonstrated to interact with transcription factors to regulate target gene expression. However, high-throughput identification of the transcription regulation relationship between transcription factors and their target genes in response to estradiol is still in its infancy. Purpose: Thus, the objective of our study was to interpret the transcription regulation network of MCF7 breast cancer cells exposed to estradiol. Methods: In this work, GSE11352 microarray data were used to identify differentially expressed genes (DEGs). Results: Our results showed that the MYB (v-myb myeloblastosis viral oncogene homolog [avian]), PGR (progesterone receptor), and MYC (v-myc myelocytomatosis viral oncogene homolog [avian]) were hub nodes in our transcriptome network, which may interact with ER and, in turn, regulate target gene expression. MYB can up-regulate MCM3 (minichromosome maintenance 3) and MCM7 expression; PGR can suppress BCL2 (B-cell lymphoma 2) expression; MYC can inhibit TGFB2 (transforming growth factor, beta 2) expression. These genes are associated with breast cancer progression via cell cycling and the $TGF{\beta}$ signaling pathway. Conclusion: Analysis of transcriptional regulation may provide a better understanding of molecular mechanisms and clues to potential therapeutic targets in the treatment of breast cancer.


Regulation network;network motif analysis;breast cancer;estradiol;microarray;transcriptome network


  1. Akar U, Chaves-Reyez A, Barria M, et al (2008). Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy, 4, 669.
  2. Albert JM, Gonzalez-Angulo AM, Guray, M, et al (2010). Estrogen/progesterone receptor negativity and HER2 positivity predict locoregional recurrence in patients with T1a, bN0 breast cancer. Int J Radiation Oncol Biol Physics, 77, 1296-302.
  3. Brandt S, Kopp A, Grage B, Knabbe C (2003). Effects of tamoxifen on transcriptional level of transforming growth factor beta (TGF-$\beta$) isoforms 1 and 2 in tumor tissue during primary treatment of patients with breast cancer. Anticancer Res, 23, 223-9.
  4. Cheng ASL, Jin VX, Fan M, et al (2006). Combinatorial analysis of transcription factor partners reveals recruitment of c-MYC to estrogen receptor-$\alpha$ responsive promoters. Molecular Cell, 21, 393-404.
  5. Chrzan P, Skokowski J, Karmolinski A, et al (2001). Amplification of c-myc gene and overexpression of c-Myc protein in breast cancer and adjacent non-neoplastic tissue. Clin Biochem, 34, 557-62.
  6. Dang CV (1999). c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol, 19, 1-11.
  7. Dawson S, Makretsov N, Blows F, et al (2010). BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer, 103, 668-75.
  8. Drabsch Y, Hugo H, Zhang R, et al (2007). Mechanism of and requirement for estrogen-regulated MYB expression in estrogen-receptor-positive breast cancer cells. Proc Natl Acad Sci U S A, 104, 13762-7.
  9. Formby B, Wiley T, et al (1998). Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53. Ann Clin Lab Sci, 28, 360-9.
  10. Ha SA, Shin SM, Namkoong H, et al (2004). Cancer-associated expression of minichromosome maintenance 3 gene in several human cancers and its involvement in tumorigenesis. Clin Cancer Res, 10, 8386-95.
  11. Huang da W, Sherman BT, Lempicki RA (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc, 4, 44-57.
  12. Jiang C, Xuan Z, Zhao F, Zhang MQ (2007). TRED: a transcriptional regulatory element database, new entries and other development. Nucleic Acids Res 35, D137-40.
  13. Kauraniemi P, Hedenfalk I, Persson K, et al (2000). MYB oncogene amplification in hereditary BRCA1 breast cancer. Cancer Res, 60, 5323-8.
  14. Klinge CM (2000). Estrogen receptor interaction with coactivators and co-repressors. Steroids, 65, 227-51.
  15. Lefebvre C, Rajbhandari P, Alvarez MJ, et al (2010). A human B-cell interactome identifies MYB and FOXM1 as master regulators of proliferation in germinal centers. Mol Syst Biol, 6, 377.
  16. Li C, Briggs MR, Ahlborn TE, et al (2001). Requirement of Sp1 and estrogen receptor $\alpha$ interaction in $17 \beta$-estradiolmediated transcriptional activation of the low density lipoprotein receptor gene expression. Endocrinology, 142, 1546-53.
  17. Matys V, Fricke E, Geffers R, et al (2003). TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res, 31, 374-8.
  18. Migliaccio A, Piccolo D, Castoria G, et al (1998). Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J, 17, 2008-18.
  19. Muller A, Kohrt HEK, Cha S, et al (2011). Long-term outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplantation of purified autologous hematopoietic stem cells. Biol Blood Marrow Transplant, 18, 125-33.
  20. Pacek M, Walter JC (2004). A requirement for MCM7 and Cdc45 in chromosome unwinding during eukaryotic DNA replication. EMBO J, 23, 3667-76.
  21. Pathiraja TN, Shetty PB, Jelinek J, et al (2011). Progesterone receptor isoform-specific promoter methylation: association of PRA promoter methylation with worse outcome in breast cancer patients. Clin Cancer Res, 17, 4177-86.
  22. Pocsfalvi G, Votta G, De Vincenzo A, et al (2011). Analysis of secretome changes uncovers an autocrine/paracrine component in the modulation of cell proliferation and motility by c-Myc. J Proteome Res, 10, 5326-37.
  23. Real PJ, Sierra A, De Juan A, et al (2002). Resistance to chemotherapy via Stat3-dependent overexpression of Bcl- 2 in metastatic breast cancer cells. Oncogene, 21, 7611-8.
  24. Ren B, Yu G, Tseng GC, et al (2006). MCM7 amplification and overexpression are associated with prostate cancer progression. Oncogene, 25, 1090-8.
  25. Shannon P, Markiel A, Ozier O, et al (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res, 13, 2498-504.
  26. Sisci D, Middea E, Morelli C, et al (2010). $17 \beta$-Estradiol enhances $\alpha$ 5 integrin subunit gene expression through ER$\alpha$-Sp1 interaction and reduces cell motility and invasion of ERα-positive breast cancer cells. Breast Cancer Res Treat, 124, 63-77.
  27. Smyth GK (2004). Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol, 3, Article3.
  28. Takei Y, Assenberg M, Tsujimoto G, Laskey R (2002). The MCM3 acetylase MCM3AP inhibits initiation, but not elongation, of DNA replication via interaction with MCM3. J Biol Chem, 277, 43121-5.
  29. Van Riggelen J, Müller J, Otto T, et al (2010). The interaction between Myc and Miz1 is required to antagonize $TGF \beta$- dependent autocrine signaling during lymphoma formation and maintenance. Genes Dev, 24, 1281-94.
  30. Vyhlidal C, Samudio I, Kladde M , Safe S (2000). Transcriptional activation of transforming growth factor alpha by estradiol: requirement for both a GC-rich site and an estrogen response element half-site. J Mol Endocrinol, 24, 329-38.
  31. Wang Y, Liu S, Zhang G, et al (2005). Knockdown of c-Myc expression by RNAi inhibits MCF-7 breast tumor cells growth in vitro and in vivo. Breast Cancer Res, 7, R220-8.
  32. Wernicke S, Rasche F (2006). FANMOD: a tool for fast network motif detection. Bioinformatics, 22, 1152-3.
  33. Wiercinska E, Naber HPH, Pardali E, et al (2011). The TGF-$\beta$/ Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res Treat, 128, 657-66.
  34. Yager JD, Davidson NE (2006). Estrogen carcinogenesis in breast cancer. New Engl J Med, 354, 270-82.
  35. Yin P, Lin Z, Cheng YH, et al (2007). Progesterone receptor regulates Bcl-2 gene expression through direct binding to its promoter region in uterine leiomyoma cells. J Clin Endocrinol Metab, 92, 4459-66.
  36. Zhao Y, Han W, Li Q, et al (2005). Mechanism of transcriptional regulation of LRP16 gene expression by 17-$\beta$ estradiol in MCF-7 human breast cancer cells. J Mol Endocrinol, 34, 77-89.

Cited by

  1. Demethylzeylasteral exhibits dose-dependent inhibitory behaviour towards estradiol glucuronidation vol.39, pp.2, 2014,
  2. RNAi-mediated knockdown of MCM7 gene on CML cells and its therapeutic potential for leukemia vol.34, pp.2, 2017,