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

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.

Nuclear Deformability Constitutes a Rate-Limiting Step During Cell Migration in 3-D Environments

“…These properties are not only relevant in various physiological processes, but are also attracting increasing interest in the study of cancer metastasis, as altered expression of lamins has been reported in a variety of human cancers (reviewed in 33 ). Breast cancer tumor cells, for example, often have reduced expression of lamins A/C, 43, 44 and loss of lamins A/C negatively correlates with disease-free survival. 43 The increased nuclear deformability associated with reduced lamin A/C levels may promote invasion of metastatic cancer cells into surrounding tissues and spreading through the vascular and lymphatic system, thereby constituting a substantial risk factor on top of gene-regulatory changes linked to altered lamin expression.…”

“…Breast cancer tumor cells, for example, often have reduced expression of lamins A/C, 43, 44 and loss of lamins A/C negatively correlates with disease-free survival. 43 The increased nuclear deformability associated with reduced lamin A/C levels may promote invasion of metastatic cancer cells into surrounding tissues and spreading through the vascular and lymphatic system, thereby constituting a substantial risk factor on top of gene-regulatory changes linked to altered lamin expression. 33 Thus, an improved understanding of the multifaceted function of lamins has the potential to uncover novel therapeutic targets in cancer metastasis and diseases caused by mutations in nuclear envelope proteins.…”

Squish and squeeze — the nucleus as a physical barrier during migration in confined environments

“…Increasing reports indicate that altered lamin expression (rather than mutations) is found in many cancers, and often correlates with negative clinical outcomes [47,86,87]. For example, reduced expression of lamin A/C has been reported in breast [88,89] and cervical cancer [90], and is correlated with an increased recurrence of stage II and III colon cancer [91] and reduced disease free survival in breast cancer [89]. However, in other cases, increased A-type lamin expression is associated with disease progression, specifically in prostate, colon and ovarian cancers [92,93].…”

The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue

“…Other work has shown that the ability of myosin-II to deform the nucleus can be a decisive factor in limiting glioma migration into brain tissue (Beadle et al, 2008;Ivkovic et al, 2012), but cancer cells in general show no universal lamina phenotype (reviewed in Foster et al, 2010). Although low levels of A-type lamin have been correlated with increased reoccurrence of colon cancers (Belt et al, 2011), A-type lamin was also found to be upregulated in certain skin and ovarian cancers (Hudson et al, 2007;Tilli et al, 2003), and higher expression of these lamin proteins has been associated with better clinical outcomes in breast cancer (Wazir et al, 2013). Our own studies of tumor expansion in mouse flank have been suggestive of an association between moderately reduced levels of A-type lamin and increased invasiveness into the surrounding tissue, but a more complex relationship between the level of A-type lamin and clinical prognosis might be explained by the tenuous balance between the effect of the lamina on nuclear deformability compared with that on cell survival.…”