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

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          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.

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          Most cited references42

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          Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival.

          Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna(-/-) mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna(-/-) mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors.
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            Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells.

            Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.
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              Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C.

              We have determined the structural organization of the human gene that encodes nuclear lamins A and C, intermediate filament proteins of the nuclear lamina. Sequencing and restriction mapping show that the coding region spans approximately 24 kilobases. The 5'-proximal promoter region contains several GC-rich stretches, a CCAAT box, and a TATA-like element of sequence TATTA. The lamin A/C gene contains 12 exons. Alternative splicing within exon 10 gives rise to two different mRNAs that code for pre-lamin A and lamin C. Consequently, two proteins are generated, only one of which, pre-lamin A, can be modified by isoprenylation. The intron positions in the human lamin A/C gene are generally conserved in the previously characterized genes for Xenopus lamin LIII and mouse lamin B2, but different from those in a Drosophila lamin gene. In the regions coding for the central rod domains, the intron positions are also conserved when compared with the intron positions in the genes for most cytoplasmic intermediate filament proteins except those for nestin and neurofilaments. Analysis of the intron positions in these genes supports the hypothesis that the nuclear lamins and other intermediate filament proteins arose from a common ancestor.
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                Author and article information

                Contributors
                kefahmokbel@hotmail.com
                Journal
                Cell Mol Biol Lett
                Cell. Mol. Biol. Lett
                Cellular & Molecular Biology Letters
                Springer Vienna (Vienna )
                1425-8153
                1689-1392
                30 November 2013
                December 2013
                : 18
                : 4
                : 595-611
                Affiliations
                [6 ]GRID grid.439666.8, London Breast Institute, , the Princess Grace Hospital, ; 45 Nottingham Place, London, W1U 5NY UK
                [1 ]GRID grid.439666.8, The London Breast Institute, , Princess Grace Hospital, ; London, UK
                [2 ]GRID grid.4464.2, ISNI 0000000121612573, Department of Breast Surgery, St. George’s Hospital and Medical School, , University of London, ; London, UK
                [3 ]Centre for Cell & Chromosome Biology, Uxbridge, London, UK
                [4 ]GRID grid.7728.a, ISNI 0000000107246933, Brunel Institute for Cancer Genetics and Pharmacogenomics, School of Health Sciences and Social Care, , Brunel University, ; Uxbridge, London, UK
                [5 ]GRID grid.5600.3, ISNI 0000000108075670, Metastasis and Angiogenesis Research Group, University Department of Surgery, Cardiff University School of Medicine, , Cardiff University, ; Cardiff, Wales, UK
                Article
                109
                10.2478/s11658-013-0109-9
                6275779
                24293108
                00c99ba2-81f0-4856-ae95-54d7bea3e8f3
                © Versita Warsaw and Springer-Verlag Wien 2013
                History
                : 23 June 2013
                : 25 November 2013
                Categories
                Research Article
                Custom metadata
                © Versita Warsaw and Springer-Verlag Wien 2013

                lamin a/c,lamin b,lamin b receptor,breast cancer,qpcr,chromosomal instability,cell senescence,cell cycle,dna repair,ageing

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