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. 2017 Oct 10;117(8):1176-1184.
doi: 10.1038/bjc.2017.261. Epub 2017 Aug 22.

Rho-GTPase activating-protein 18: a biomarker associated with good prognosis in invasive breast cancer

Mohammed A Aleskandarany  1   2 , Sultan Sonbul  1 , Rachel Surridge  1 , Abhik Mukherjee  1 , Carlos Caldas  3 , Maria Diez-Rodriguez  1 , Ibraheem Ashankyty  4 , Khalil I Albrahim  4 , Ahmed M Elmouna  4 , Ritu Aneja  5 , Stewart G Martin  1 , Ian O Ellis  1 , Andrew R Green  1 , Emad A Rakha  1   2
Affiliations

Rho-GTPase activating-protein 18: a biomarker associated with good prognosis in invasive breast cancer

Mohammed A Aleskandarany et al. Br J Cancer. .

Abstract

Background: The prognostic value of lymphovascular invasion (LVI) in breast cancer (BC) has been demonstrated in several independent studies. However, identification of driver molecules for LVI remains a challenging task. Large-scale transcriptomic profiling of histologically validated LVI can potentially identify genes that regulate LVI.

Methods: Integrative bio-informatics analyses of the METABRIC study were performed utilising a subset of strictly defined LVI using histological and immunohistochemical (IHC) criteria. ARHGAP18 was among the top differentially expressed genes between LVI+ and LVI- BC with a 1.8-fold change. The prognostic impact of ARHGAP18 gene expression was assessed in the METABRIC data set (n=1980) and externally validated using the online BC gene expression data sets utilising bc-GenExMiner v4.0 (n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large cohort of invasive BC (n=959) with long-term follow-up using IHC.

Results: Pooled analysis of ARHGAP18 mRNA expression showed that overexpression was associated with better outcome (P<0.001, hazard ratio (HR)=0.82, 95% CI 0.75-0.90). ARHGAP18 protein was expressed in the cytoplasm and nuclei of the tumour cells and its expression was positively associated with good prognostic variables. Lack of cytoplasmic expression showed associations with LVI (P=0.006), epithelial-mesenchymal transition and the HER+ subtype (P=0.01). Loss of nuclear expression was associated with higher grade, HER2+ and high Ki67LI (P=0.001). Cytoplasmic and nuclear expression showed a positive association with improved survival independent of other variables (P=0.01, HR=0.74, 95% CI 0.60-87).

Conclusions: ARHGAP18 expression at transcriptomic and protein levels is associated with improved patients' outcomes whose deregulation may play a role in tumour progression and the development of LVI in BC. Further assessment of its potential therapeutic value in BC is warranted.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Western blot and immunohistochemical expression of ARHGAP18 in BC. (A) Western blot of ARHGAP18 and the housekeeping Beta-actin. Western blotting performed on whole cell lysates of HeLa CCL-2 and MDA-MB-231 (lanes 1 and 2, respectively). Primary antibody (Anti-ARHGAP18, 1 : 1000 dilution), and of the HRP-labelled secondary anti-rabbit antibody (1 : 15 000), with β-actin (1 : 2000, lanes 3 and 4) used as a loading control. The images were developed via chemiluminescence using an Odyssesy Fc (Li-cor Bisosciences, USA). (B–D) Immunohistochemical expression of ARHGAP18 in invasive BC: (B) Negative, (C) Invasive BC case showing positive cytoplasmic expression, and (D) a case of invasive BC case showing both nuclear and cytoplasmic expression.
Figure 2
Figure 2
Kaplan–Meier plots of the association between cytoplasmic ARHGAP18 expression and BCSS and time to distant metastasis during the follow-up period.
Figure 3
Figure 3
Kaplan–Meier plots of the association between nuclear ARHGAP18 expression and BCSS and time to distant metastasis during the follow-up period.
See this image and copyright information in PMC

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References

    1. Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JFR, Macmillan D, Blamey RW, Ellis IO (2005) 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(3): 340–350. - PubMed
    1. Albasri A, Seth R, Jackson D, Benhasouna A, Crook S, Nateri AS, Chapman R, Ilyas M (2009) C-terminal Tensin-like (CTEN) is an oncogene which alters cell motility possibly through repression of E-cadherin in colorectal cancer. J Pathol 218(1): 57–65. - PubMed
    1. Aleskandarany MA, Sonbul SN, Mukherjee A, Rakha EA (2015) Molecular mechanisms underlying lymphovascular invasion in invasive breast cancer. Pathobiology 82(3-4): 113–123. - PubMed
    1. Altman DG, Bland JM (1994) Statistics notes: diagnostic tests 2: predictive values. BMJ 309(6947): 102. - PMC - PubMed
    1. Barcellos KS, Bigarella CL, Wagner MV, Vieira KP, Lazarini M, Langford PR, Machado-Neto JA, Call SG, Staley DM, Chung JY, Hansen MD, Saad ST (2013) ARHGAP21 protein, a new partner of alpha-tubulin involved in cell-cell adhesion formation and essential for epithelial-mesenchymal transition. J Biol Chem 288(4): 2179–2189. - PMC - PubMed

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