Skip to main content
Download PDF
  • Research article
  • Published:

The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer

Cellular & Molecular Biology Letters volume 18, pages 595–611 (2013)Cite this article

Abstract

Lamin A/C (LMNA), lamin B1 (LMNB1) and lamin B receptor (LBR) have key roles in nuclear structural integrity and chromosomal stability. In this study, we have studied the relationships between the mRNA expressions of A-type lamins, LMNB1 and LBR and the clinicopathological parameters in human breast cancer. Samples of breast cancer tissues (n = 115) and associated non-cancerous tissue (ANCT; n = 30) were assessed using reverse transcription and quantitative PCR. Transcript levels were correlated with clinicopathological data. Higher levels of A-type lamins and LMNB1 mRNA expression were seen in ANCT. Higher lamin A/C expression was associated with the early clinical stage (TNM1 vs. TNM3 — 13 vs. 0.21; p = 0.0515), with better clinical outcomes (disease-free survival vs. mortality — 11 vs. 1; p = 0.0326), and with better overall (p = 0.004) and disease-free survival (p = 0.062). The expression of LMNB1 declined with worsening clinical outcome (disease-free vs. mortalities — 0.0011 vs. 0.000; p = 0.0177). LBR mRNA expression was directly associated with tumor grade (grade 1 vs. grade 3 — 0.00 vs. 0.00; p = 0.0479) and Nottingham Prognostic Index (NPI1 vs. NPI3 — 0.00 vs. 0.00; p = 0.0551). To the best of our knowledge, this is the first study to suggest such a role for A-type lamins, lamin B1 and LBR in human breast cancer, identifying an important area for further research.

Abbreviations

CI:

confidence interval

CK19:

cytokeratin 19

DF:

disease-free survival

DR:

distant disease recurrence

LBR:ANCT:

associated non-cancerous tissue, lamin B receptor

LMDM:

lamin B deficient micro-domains

LR:

local disease recurrence

mTOR:

mammalian target of rapamycin

NPI:

Nottingham Prognostic Index

qPCR:

quantitative polymerase chain reaction

TNM:

clinical stage according to tumor size, nodal status and presence of distant metastases

References

  1. Bridger, J.M., Foeger, N., Kill, I.R. and Herrmann, H. The nuclear lamina. Both a structural framework and a platform for genome organization. FEBS J.274 (2007) 1354–1361.

    Article  CAS  PubMed  Google Scholar 

  2. Guelen, L., Pagie, L., Brasset, E., Meuleman, W., Faza, M.B., Talhout, W., Eussen, B.H., de Klein, A., Wessels, L., de Laat, W. and van Steensel, B. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453 (2008) 948–951. DOI: 10.1038/nature06947.

    Article  CAS  PubMed  Google Scholar 

  3. Malhas, A., Lee, C.F., Sanders, R., Saunders, N.J. and Vaux, D.J. Defects in lamin B1 expression or processing affect interphase chromosome position and gene expression. J. Cell Biol. 176 (2007) 593–603. DOI: 10.1083/jcb.200607054.

    Article  CAS  PubMed  Google Scholar 

  4. Bridger, J.M., Kill, I.R., O’Farrell, M. and Hutchison, C.J. Internal lamin structures within G1 nuclei of human dermal fibroblasts. J. Cell Sci. 104 (1993) 297–306.

    CAS  PubMed  Google Scholar 

  5. Goldman, A.E., Moir, R.D., Montag-Lowy, M., Stewart, M. and Goldman, R.D. Pathway of incorporation of microinjected lamin A into the nuclear envelope. J. Cell Biol. 119 (1992) 725–735.

    Article  CAS  PubMed  Google Scholar 

  6. Solovei, I., Wang, A.S., Thanisch, K., Schmidt, C.S., Krebs, S., Zwerger, M., Cohen, T.V., Devys, D., Foisner, R., Peichl, L., Herrmann, H., Blum, H., Engelkamp, D., Stewart, C.L., Leonhardt, H. and Joffe, B. LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell 152 (2013) 584–598. DOI: 10.1016/j.cell.2013.01.009.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang, H., Kieckhaefer, J.E. and Cao, K. Mouse models of laminopathies. Aging Cell 12 (2013) 2–10. DOI: 10.1111/acel.12021.

    Article  CAS  PubMed  Google Scholar 

  8. Worman, H.J., Ostlund, C. and Wang, Y. Diseases of the nuclear envelope. Cold Spring Harb. Perspect. Biol. 2 (2010) a000760. DOI: 10.1101/cshperspect.a000760.

    Article  PubMed  Google Scholar 

  9. Chi, Y.H., Chen, Z.J. and Jeang, K.T. The nuclear envelopathies and human diseases. J. Biomed. Sci. 16 (2009) 96. DOI: 10.1186/1423-0127-16-96.

    Article  PubMed  Google Scholar 

  10. Kong, L., Schafer, G., Bu, H., Zhang, Y. and Klocker, H. Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway. Carcinogenesis 33 (2012) 751–759. DOI: 10.1093/carcin/bgs022.

    Article  CAS  PubMed  Google Scholar 

  11. Helfand, B.T., Wang, Y., Pfleghaar, K., Shimi, T., Taimen, P. and Shumaker, D.K. Chromosomal regions associated with prostate cancer risk localize to lamin B-deficient microdomains and exhibit reduced gene transcription. J. Pathol. 226 (2012) 735–745. DOI: 10.1002/path.3033.

    Article  CAS  PubMed  Google Scholar 

  12. Luk, J.M. and Liu, A.M. Proteomics of hepatocellular carcinoma in Chinese patients. OMICS 15 (2011) 261–266. DOI: 10.1089/omi.2010.0099.

    Article  CAS  PubMed  Google Scholar 

  13. Al Sarakbi, W., Sasi, W., Jiang, W.G., Roberts, T., Newbold, R.F. and Mokbel, K. The mRNA expression of SETD2 in human breast cancer: correlation with clinico-pathological parameters. BMC Cancer 9 (2009) 290. DOI: 10.1186/1471-2407-9-290.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Elkak, A., Mokbel, R., Wilson, C., Jiang, W.G., Newbold, R.F. and Mokbel, K. hTERT mRNA expression is associated with a poor clinical outcome in human breast cancer. Anticancer Res. 26 (2006) 4901–4904.

    CAS  PubMed  Google Scholar 

  15. Wazir, U., Jiang, W.G., Sharma, A.K. and Mokbel, K. The mRNA expression of DAP3 in human breast cancer: correlation with clinicopathological parameters. Anticancer Res. 32 (2012) 671–674.

    CAS  PubMed  Google Scholar 

  16. Jiang, W.G., Watkins, G., Lane, J., Cunnick, G.H., Douglas-Jones, A., Mokbel, K. and Mansel, R.E. Prognostic value of rho GTPases and rho guanine nucleotide dissociation inhibitors in human breast cancers. Clin. Cancer Res. 9 (2003) 6432–6440.

    CAS  PubMed  Google Scholar 

  17. Lin, F. and Worman, H.J. Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J. Biol. Chem. 268 (1993) 16321–16326.

    CAS  PubMed  Google Scholar 

  18. Bonne, G., Di Barletta, M.R., Varnous, S., Becane, H.M., Hammouda, E.H., Merlini, L., Muntoni, F., Greenberg, C.R., Gary, F., Urtizberea, J.A., Duboc, D., Fardeau, M., Toniolo, D. and Schwartz, K. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat. Genet. 21 (1999) 285–288. DOI: 10.1038/6799.

    Article  CAS  PubMed  Google Scholar 

  19. Maraldi, N.M., Capanni, C., Cenni, V., Fini, M. and Lattanzi, G. Laminopathies and lamin-associated signaling pathways. J. Cell Biochem.112 (2011) 979–992. DOI: 10.1002/jcb.22992.

    Article  CAS  PubMed  Google Scholar 

  20. Cenni, V., Capanni, C., Columbaro, M., Ortolani, M., D’Apice, M.R., Novelli, G., Fini, M., Marmiroli, S., Scarano, E., Maraldi, N.M., Squarzoni, S., Prencipe, S. and Lattanzi, G. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria. Eur. J. Histochem. 55 (2011) e36. DOI: 10.4081/ejh.2011.e36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Cao, K., Graziotto, J.J., Blair, C.D., Mazzulli, J.R., Erdos, M.R., Krainc, D. and Collins, F.S. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci. Transl. Med. 3 (2011) 89ra58. DOI: 10.1126/scitranslmed.3002346.

    CAS  PubMed  Google Scholar 

  22. Ramos, F.J., Chen, S.C., Garelick, M.G., Dai, D.F., Liao, C.Y., Schreiber, K.H., MacKay, V.L., An, E.H., Strong, R., Ladiges, W.C., Rabinovitch, P.S., Kaeberlein, M. and Kennedy, B.K. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci. Transl. Med. 4 (2012) 144ra103. DOI: 10.1126/scitranslmed.3003802.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Wydner, K.L., McNeil, J.A., Lin, F., Worman, H.J. and Lawrence, J.B. Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization. Genomics 32 (1996) 474–478. DOI: 10.1006/geno.1996.0146.

    Article  CAS  PubMed  Google Scholar 

  24. Tsai, M.Y., Wang, S., Heidinger, J.M., Shumaker, D.K., Adam, S.A., Goldman, R.D. and Zheng, Y. A mitotic lamin B matrix induced by RanGTP required for spindle assembly. Science 311 (2006) 1887–1893. DOI: 10.1126/science.1122771.

    Article  CAS  PubMed  Google Scholar 

  25. Worman, H.J. and Bonne, G. “laminopathies”: a wide spectrum of human diseases. Exp. Cell Res. 313 (2007) 2121–2133. DOI: 10.1016/j.yexcr.2007.03.028.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Young, S.G., Jung, H.J., Coffinier, C. and Fong, L.G. Understanding the roles of nuclear A- and B-type lamins in brain development. J. Biol. Chem.287 (2012) 16103–16110. DOI: 10.1074/jbc.R112.354407.

    Article  CAS  PubMed  Google Scholar 

  27. Coffeen, C.M., McKenna, C.E., Koeppen, A.H., Plaster, N.M., Maragakis, N., Mihalopoulos, J., Schwankhaus, J.D., Flanigan, K.M., Gregg, R.G., Ptacek, L.J. and Fu, Y.H. Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31. Hum. Mol. Genet. 9 (2000) 787–793.

    Article  CAS  PubMed  Google Scholar 

  28. Hegele, R.A., Cao, H., Liu, D.M., Costain, G.A., Charlton-Menys, V., Rodger, N.W. and Durrington, P.N. Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy. Am. J. Hum. Genet. 79 (2006) 383–389. DOI: 10.1086/505885.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Olins, A.L., Rhodes, G., Welch, D.B., Zwerger, M. and Olins, D.E. Lamin B receptor: multi-tasking at the nuclear envelope. Nucleus 1 (2010) 53–70. DOI: 10.4161/nucl.1.1.10515.

    PubMed  Google Scholar 

  30. Hoffmann, K., Sperling, K., Olins, A.L. and Olins, D.E. The granulocyte nucleus and lamin B receptor: avoiding the ovoid. Chromosoma 116 (2007) 227–235. DOI: 10.1007/s00412-007-0094-8.

    Article  CAS  PubMed  Google Scholar 

  31. Waterham, H.R., Koster, J., Mooyer, P., Noort Gv, G., Kelley, R.I. and Wilcox, W.R. Autosomal recessive hem/greenberg skeletal dysplasia is caused by 3betahydroxysterol delta 14-reductase deficiency due to mutations in the lamin b receptor gene. Am. J. Hum. Genet. 72 (2003) 1013–1017.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Butin-Israeli, V., Adam, S.A., Goldman, A.E. and Goldman, R.D. Nuclear lamin functions and disease. Trends Genet. 28 (2012) 464–471. DOI: 10.1016/j.tig.2012.06.001.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Fischer, A.H., Taysavang, P., Weber, C.J. and Wilson, K.L. Nuclear envelope organization in papillary thyroid carcinoma. Histol. Histopathol.16 (2001) 1–14.

    CAS  PubMed  Google Scholar 

  34. Foster, C.R., Robson, J.L., Simon, W.J., Twigg, J., Cruikshank, D., Wilson, R.G. and Hutchison, C.J. The role of lamin A in cytoskeleton organization in colorectal cancer cells: a proteomic investigation. Nucleus 2 (2011) 434–443. DOI: 10.4161/nucl.2.5.17775.

    Article  PubMed  Google Scholar 

  35. Willis, N.D., Cox, T.R., Rahman-Casans, S.F., Smits, K., Przyborski, S.A., van den Brandt, P., van Engeland, M., Weijenberg, M., Wilson, R.G., de Bruine, A. and Hutchison, C.J. Lamin A/C is a risk biomarker in colorectal cancer. PLoS ONE 3 (2008) e2988. DOI: 10.1371/journal.pone.0002988.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Hudson, M.E., Pozdnyakova, I., Haines, K., Mor, G. and Snyder, M. Identification of differentially expressed proteins in ovarian cancer using high-density protein microarrays. Proc. Natl. Acad. Sci. U S A 104 (2007) 17494–17499. DOI: 10.1073/pnas.0708572104.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Kaufmann, S.H., Mabry, M., Jasti, R. and Shaper, J.H. Differential expression of nuclear envelope lamins A and C in human lung cancer cell lines. Cancer Res. 51 (1991) 581–586.

    CAS  PubMed  Google Scholar 

  38. Broers, J.L., Raymond, Y., Rot, M.K., Kuijpers, H., Wagenaar, S.S. and Ramaekers, F.C. Nuclear A-type lamins are differentially expressed in human lung cancer subtypes. Am. J. Pathol. 143 (1993) 211–220.

    CAS  PubMed  Google Scholar 

  39. Moss, S.F., Krivosheyev, V., de Souza, A., Chin, K., Gaetz, H.P., Chaudhary, N., Worman, H.J. and Holt, P.R. Decreased and aberrant nuclear lamin expression in gastrointestinal tract neoplasms. Gut 45 (1999) 723–729.

    Article  CAS  PubMed  Google Scholar 

  40. Venables, R.S., McLean, S., Luny, D., Moteleb, E., Morley, S., Quinlan, R.A., Lane, E.B. and Hutchison, C.J. Expression of individual lamins in basal cell carcinomas of the skin. Br. J. Cancer 84 (2001) 512–519. DOI: 10.1054/bjoc.2000.1632.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Capo-chichi, C.D., Cai, K.Q., Simpkins, F., Ganjei-Azar, P., Godwin, A.K. and Xu, X.X. Nuclear envelope structural defects cause chromosomal numerical instability and aneuploidy in ovarian cancer. BMC Med. 9 (2011) 28. DOI: 10.1186/1741-7015-9-28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Wu, Z., Wu, L., Weng, D., Xu, D., Geng, J. and Zhao, F. Reduced expression of lamin A/C correlates with poor histological differentiation and prognosis in primary gastric carcinoma. J. Exp. Clin. Cancer Res. 28 (2009) 8. DOI: 10.1186/1756-9966-28-8.

    Article  PubMed  Google Scholar 

  43. Agrelo, R., Setien, F., Espada, J., Artiga, M.J., Rodriguez, M., Perez-Rosado, A., Sanchez-Aguilera, A., Fraga, M.F., Piris, M.A. and Esteller, M. Inactivation of the lamin A/C gene by CpG island promoter hypermethylation in hematologic malignancies, and its association with poor survival in nodal diffuse large B-cell lymphoma. J. Clin. Oncol. 23 (2005) 3940–3947. DOI: 10.1200/JCO.2005.11.650.

    Article  CAS  PubMed  Google Scholar 

  44. Wong, K.F. and Luk, J.M. Discovery of lamin B1 and vimentin as circulating biomarkers for early hepatocellular carcinoma. Methods Mol. Biol. 909 (2012) 295–310. DOI: 10.1007/978-1-61779-959-4_19.

    CAS  PubMed  Google Scholar 

  45. Sun, S., Xu, M.Z., Poon, R.T., Day, P.J. and Luk, J.M. Circulating lamin B1 (LMNB1) biomarker detects early stages of liver cancer in patients. J. Proteome Res. 9 (2010) 70–78. DOI: 10.1021/pr9002118.

    Article  CAS  PubMed  Google Scholar 

  46. Coradeghini, R., Barboro, P., Rubagotti, A., Boccardo, F., Parodi, S., Carmignani, G., D’Arrigo, C., Patrone, E. and Balbi, C. Differential expression of nuclear lamins in normal and cancerous prostate tissues. Oncol. Rep. 15 (2006) 609–613.

    CAS  PubMed  Google Scholar 

  47. Wazir, U., Newbold, R.F., Jiang, W.G., Sharma, A.K. and Mokbel, K. Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer. Oncol. Rep. 29 (2013) 1969–1974. DOI: 10.3892/or.2013.2346.

    CAS  PubMed  Google Scholar 

  48. Wander, S.A., Zhao, D., Besser, A.H., Hong, F., Wei, J., Ince, T.A., Milikowski, C., Bishopric, N.H., Minn, A.J., Creighton, C.J. and Slingerland, J.M. PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy. Breast Cancer Res. Treat. (2013) 369–381. DOI: 10.1007/s10549-012-2389-6.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. London Breast Institute, the Princess Grace Hospital, 45 Nottingham Place, London, W1U 5NY, UK

    Kefah Mokbel

  2. The London Breast Institute, Princess Grace Hospital, London, UK

    Umar Wazir, Anup K. Sharma & Kefah Mokbel

  3. Department of Breast Surgery, St. George’s Hospital and Medical School, University of London, London, UK

    Umar Wazir & Kefah Mokbel

  4. Centre for Cell & Chromosome Biology, Uxbridge, London, UK

    Mai Hassan Ahmed & Joanna M. Bridger

  5. Brunel Institute for Cancer Genetics and Pharmacogenomics, School of Health Sciences and Social Care, Brunel University, Uxbridge, London, UK

    Mai Hassan Ahmed & Amanda Harvey

  6. Metastasis and Angiogenesis Research Group, University Department of Surgery, Cardiff University School of Medicine, Cardiff University, Cardiff, Wales, UK

    Wen G. Jiang

Authors
  1. Umar Wazir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mai Hassan Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joanna M. Bridger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amanda Harvey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen G. Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anup K. Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kefah Mokbel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kefah Mokbel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wazir, U., Ahmed, M.H., Bridger, J.M. et al. The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer. Cell Mol Biol Lett 18, 595–611 (2013). https://doi.org/10.2478/s11658-013-0109-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11658-013-0109-9

Key words

Cellular & Molecular Biology Letters

ISSN: 1689-1392

Contact us