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

Umar Wazir, Mai Ahmed, Joanna Bridger 4 , Amanda Harvey 5 , Wen Jiang 6 , Anup Sharma 2 , and Kefah Mokbel
  • 1 London Breast Institute, the Princess Grace Hospital, 45 Nottingham Place, London, W1U 5NY, UK
  • 2 The London Breast Institute, Princess Grace Hospital, London, UK
  • 3 Department of Breast Surgery, St. George’s Hospital and Medical School, University of London, London, UK
  • 4 Centre for Cell & Chromosome Biology, Uxbridge, London, UK
  • 5 Brunel Institute for Cancer Genetics and Pharmacogenomics, School of Health Sciences and Social Care, Brunel University, Uxbridge, London, UK
  • 6 Metastasis and Angiogenesis Research Group, University Department of Surgery, Cardiff University School of Medicine, Cardiff University, Cardiff, Wales, UK


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.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

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

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.

  • [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.


Journal + Issues