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Epidemiology

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

British Journal of Cancervolume 118pages11421151 (2018) | Download Citation

Abstract

Background

Mediator complex (MED) proteins have a key role in transcriptional regulation, some interacting with the oestrogen receptor (ER). Interrogation of the METABRIC cohort suggested that MED7 may regulate lymphovascular invasion (LVI). Thus MED7 expression was assessed in large breast cancer (BC) cohorts to determine clinicopathological significance.

Methods

MED7 gene expression was investigated in the METABRIC cohort (n = 1980) and externally validated using bc-GenExMiner v4.0. Immunohistochemical expression was assessed in the Nottingham primary BC series (n = 1280). Associations with clinicopathological variables and patient outcome were evaluated.

Results

High MED7 mRNA and protein expression was associated with good prognostic factors: low grade, smaller tumour size, good NPI, positive hormone receptor status (p < 0.001), and negative LVI (p = 0.04) status. Higher MED7 protein expression was associated with improved BC-specific survival within the whole cohort and ER+/luminal subgroup. Pooled MED7 gene expression data in the external validation cohort confirmed association with better survival, corroborating with the protein expression. On multivariate analysis, MED7 protein was independently predictive of longer BC-specific survival in the whole cohort and Luminal A subtype (p < 0.001).

Conclusions

MED7 is an important prognostic marker in BC, particularly in ER+luminal subtypes, associated with improved survival and warrants future functional analysis.

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Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International licence (CC BY 4.0).

References

  1. 1.

    Dawson, S. J., Rueda, O. M., Aparicio, S. & Caldas, C. A new genome-driven integrated classification of breast cancer and its implications. EMBO J. 32, 617–628 (2013).

  2. 2.

    Mohammed, R. A. A. et al. Improved methods of detection of lymphovascular invasion demonstrate that it is the predominant method of vascular invasion in breast cancer and has important clinical consequences. Am. J. Surg. Pathol. 31, 1825–1833 (2007).

  3. 3.

    Rakha, E. A. et al. The prognostic significance of lymphovascular invasion in invasive breast carcinoma. Cancer 118, 3670–3680 (2012).

  4. 4.

    Karaman, S. & Detmar, M. Mechanisms of lymphatic metastasis. J. Clin. Invest. 124, 922–928 (2014).

  5. 5.

    Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).

  6. 6.

    Gustafsson, C. M. & Samuelsson, T. Mediator--a universal complex in transcriptional regulation. Mol. Microbiol. 41, 1–8 (2001).

  7. 7.

    Woychik, N. A. & Hampsey, M. The RNA polymerase II machinery: structure illuminates function. Cell 108, 453–463 (2002).

  8. 8.

    Schiano, C. et al. Involvement of Mediator complex in malignancy. Biochim. Biophys. Acta 1845, 66–83 (2014).

  9. 9.

    Kwon, J. Y. et al. Caenorhabditis elegans mediator complexes are required for developmental-specific transcriptional activation. Proc. Natl. Acad. Sci. USA 96, 14990–14995 (1999).

  10. 10.

    Tebbji, F. et al. A functional portrait of Med7 and the mediator complex in Candida albicans. PLoS Genet. 10, e1004770 (2014).

  11. 11.

    Koschubs, T. et al. Identification, structure, and functional requirement of the Mediator submodule Med7N/31. EMBO J. 28, 69–80 (2009).

  12. 12.

    Hur, K., Lee, H. J., Woo, J. H., Kim, J. H. & Yang, H. K. Gene expression profiling of human gastrointestinal stromal tumors according to its malignant potential. Dig. Dis. Sci. 55, 2561–2567 (2010).

  13. 13.

    Fidalgo, F. et al. Lymphovascular invasion and histologic grade are associated with specific genomic profiles in invasive carcinomas of the breast. Tumour Biol. 36, 1835–1848 (2015).

  14. 14.

    Hasegawa, N. et al. Mediator subunits MED1 and MED24 cooperatively contribute to pubertal mammary gland development and growth of breast carcinoma cells. Mol. Cell. Biol. 32, 1483–1495 (2012).

  15. 15.

    Ciriello, G. et al. The molecular diversity of Luminal A breast tumors. Breast Cancer Res. Treat. 141, 409–420 (2013).

  16. 16.

    Stingl, J. & Caldas, C. Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nat. Rev. Cancer 7, 791–799 (2007).

  17. 17.

    Silwal-Pandit, L. et al. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin. Cancer Res. 20, 3569–3580 (2014).

  18. 18.

    Jezequel, P. et al. bc-GenExMiner: an easy-to-use online platform for gene prognostic analyses in breast cancer. Breast Cancer Res. Treat. 131, 765–775 (2012).

  19. 19.

    Aleskandarany, M. A. et al. Prognostic significance of androgen receptor expression in invasive breast cancer: transcriptomic and protein expression analysis. Breast Cancer Res. Treat. 159, 215–227 (2016a).

  20. 20.

    Abd El-Rehim, D. M. et al. High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int. J. Cancer 116, 340–350 (2005).

  21. 21.

    Rakha, E. A. et al. Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin. Cancer Res. 15, 2302–2310 (2009).

  22. 22.

    McCarty, K. S. Jr. & McCarty, K. S. Sr. Histochemical approaches to steroid receptor analyses. Semin. Diagn. Pathol. 1, 297–308 (1984).

  23. 23.

    Barros, F. F. T. et al. Characterisation of HER heterodimers in breast cancer using in situ proximity ligation assay. Breast Cancer Res. Treat. 144, 273–285 (2014).

  24. 24.

    Elsheikh, S. et al. CCND1 amplification and cyclin D1 expression in breast cancer and their relation with proteomic subgroups and patient outcome. Breast Cancer Res. Treat. 109, 325–335 (2008).

  25. 25.

    Habashy, H. O., Rakha, E. A., Ellis, I. O. & Powe, D. G. The oestrogen receptor coactivator CARM1 has an oncogenic effect and is associated with poor prognosis in breast cancer. Breast Cancer Res. Treat. 140, 307–316 (2013).

  26. 26.

    Rakha, E. A. et al. Prognostic markers in triple-negative breast cancer. Cancer 109, 25–32 (2007).

  27. 27.

    Aleskandarany, M. A. et al Prognostic value of proliferation assay in the luminal, HER2-positive, and triple-negative biologic classes of breast cancer. Breast Cancer Res. 14, R3 (2012).

  28. 28.

    Aleskandarany, M. A. et al. Growth fraction as a predictor of response to chemotherapy in node-negative breast cancer. Int. J. Cancer 126, 1761–1769 (2010a).

  29. 29.

    Aleskandarany, M. A. et al. Clinicopathologic and molecular significance of phospho-Akt expression in early invasive breast cancer. Breast Cancer Res. Treat. 127, 407–416 (2011).

  30. 30.

    Aleskandarany, M. A. et al. PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis. Breast Cancer Res. Treat. 122, 45–53 (2010b).

  31. 31.

    Al-Dhaheri, M. et al. CARM1 is an important determinant of ER alpha-dependent breast cancer cell differentiation and proliferation in breast cancer cells. Cancer Res. 71, 2118–2128 (2011).

  32. 32.

    Hurtado, A., Holmes, K. A., Ross-Innes, C. S., Schmidt, D. & Carroll, J. S. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat. Genet. 43, 27–U42 (2011).

  33. 33.

    Habashy, H. O. et al. RERG (Ras-like, oestrogen-regulated, growth-inhibitor) expression in breast cancer: a marker of ER-positive luminal-like subtype. Breast Cancer Res. Treat. 128, 315–326 (2011).

  34. 34.

    Aleskandarany, M. A. et al. The prognostic significance of STAT3 in invasive breast cancer: analysis of protein and mRNA expressions in large cohorts. Breast Cancer Res. Treat. 156, 9–20 (2016b).

  35. 35.

    Voduc, D., Cheang, M. & Nielsen, T. GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value. Cancer Epidemiol. Biomarkers Prev. 17, 365–373 (2008).

  36. 36.

    Nagarajan, S., Benito, E., Fischer, A. & Johnsen, S. A. H4K12ac is regulated by estrogen receptor-alpha and is associated with BRD4 function and inducible transcription. Oncotarget 6, 7305–7317 (2015).

  37. 37.

    Zhang, L. et al Silencing MED1 sensitizes breast cancer cells to pure anti-estrogen fulvestrant in vitro and in vivo. PLoS ONE 8, e70641 (2013).

  38. 38.

    Lien, H. C., Huang, C. S., Yang, Y. W. & Jeng, Y. M. MED12 exon 2 mutation as a highly sensitive and specific marker in distinguishing phyllodes tumours from other spindle neoplasms of the breast. APMIS 124, 356–364 (2016).

  39. 39.

    Haltas, H. et al. Invasive lobular carcinoma with extracellular mucin as a distinct variant of lobular carcinoma: a case report. Diagn. Pathol. 7, 91 (2012).

  40. 40.

    Rakha, E. A. et al. Histologic grading is an independent prognostic factor in invasive lobular carcinoma of the breast. Breast Cancer Res. Treat. 111, 121–127 (2008).

  41. 41.

    Yu, J., Dabbs, D. J., Shuai, Y., Niemeier, L. A. & Bhargava, R. Classical-type invasive lobular carcinoma with HER2 overexpression: clinical, histologic, and hormone receptor characteristics. Am. J. Clin. Pathol. 136, 88–97 (2011).

  42. 42.

    Abdel-Fatah, T. M. et al. Morphologic and molecular evolutionary pathways of low nuclear grade invasive breast cancers and their putative precursor lesions: further evidence to support the concept of low nuclear grade breast neoplasia family. Am. J. Surg. Pathol. 32, 513–523 (2008).

  43. 43.

    Ryu, S. J., Zhou, S., Ladurner, A. G. & Tjian, R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397, 446–450 (1999).

  44. 44.

    Finlin, B. S. et al. RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer. J. Biol. Chem. 276, 42259–42267 (2001).

  45. 45.

    Laganiere, J. et al. From the cover: location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. Proc. Natl. Acad. Sci. USA 102, 11651–11656 (2005).

  46. 46.

    Masuda, H. et al. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res. Treat. 136, 331–345 (2012).

  47. 47.

    ElTanani, M. K. K. & Green, C. D. Two separate mechanisms for ligand-independent activation of the estrogen receptor. Mol. Endocrinol. 11, 928–937 (1997).

  48. 48.

    Dumont, A. G., Dumont, S. N. & Trent, J. C. The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer. Chin. J. Cancer 31, 327–334 (2012).

  49. 49.

    Lee, A. K. C., Delellis, R. A., Silverman, M. L., Heatley, G. J. & Wolfe, H. J. Prognostic-significance of peritumoral lymphatic and blood-vessel invasion in node-negative carcinoma of the breast. J. Clin. Oncol. 8, 1457–1465 (1990).

  50. 50.

    Hulit, J. et al. N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. Cancer Res. 67, 3106–3116 (2007).

  51. 51.

    Alshareeda, A. T. et al. Characteristics of basal cytokeratin expression in breast cancer. Breast Cancer Res. Treat. 139, 23–37 (2013).

  52. 52.

    Szyf, M. DNA methylation signatures for breast cancer classification and prognosis. Genome Med. 4, 26 (2012).

  53. 53.

    Dumitrescu, R. G. DNA methylation and histone modifications in breast cancer. Methods Mol. Biol. 863, 35–45 (2012).

  54. 54.

    Parthun, M. R. Hat1: the emerging cellular roles of a type B histone acetyltransferase. Oncogene 26, 5319–5328 (2007).

  55. 55.

    Xiao, B. et al. Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature 421, 652–656 (2003).

  56. 56.

    Elsheikh, S. E. et al. Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res. 69, 3802–3809 (2009).

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Acknowledgements

A.M. acknowledges the NIHR, the Academy of Medical Sciences and the Pathological Society of GB and Ireland for support. The authors thank the Nottingham Health Science Biobank, Nottingham City Hospital NHS Trust and the Breast Cancer Now Tissue Bank for the provision of tissues used in this study.

Author information

Affiliations

  1. Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, NG5 1PB, UK

    • Chitra Joseph
    • , Olivia Macnamara
    • , Madeleine Craze
    • , Christopher C. Nolan
    • , Maria Diez-Rodriguez
    • , Sultan N. Sonbul
    • , Mohammed A. Aleskandarany
    • , Andrew R. Green
    • , Emad A. Rakha
    • , Ian O. Ellis
    •  & Abhik Mukherjee
  2. CRUK Cambridge Research Institute, Cambridge, UK

    • Roslin Russell
  3. Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

    • Elena Provenzano

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Contributions

C.J. participated in its design, experimentation, analysis, interpretation and manuscript drafting. O.M. conducted the immunohistochemical studies and participated in the analysis and interpretation. M.C. and S.S. helped in data management and interpretation; R.R. carried out the molecular genetics analysis; E.P. helped with pathology review and manuscript drafting; C.C.N. and M.D.-R. helped with the TMA sections; M.A. helped in immune-histochemical analysis and interpretation; I.O.E., A.G. and E.A.R. participated in interpretation and manuscript drafting. A.M. conceived and supervised the study and participated in its design, interpretation and analysis, including drafting. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Abhik Mukherjee.

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https://doi.org/10.1038/s41416-018-0041-x

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