Abstract
Our previous study demonstrated that upregulation of multiple epidermal growth factor-like domains 11 (MEGF11) gene expression is involved in the mechanism by which recurrence of Triple Negative Breast Cancer (TNBC) occurs. Our aim was to elucidate the role of MEGF11 expression in TNBC cells, both in vitro and in vivo, and in human tissue. Following MEGF11 gene knockdown (∆MEGF11) or over-expression in MDA-MB-231 and MB-468 cells, cell growth and chemokine gene expression were evaluated. In vivo, tumour growth of implanted human TNBC cells and the number of circulating 4T1 mouse tumour cells were measured. There was a significant decrease in cell growth via inhibition of AKT, NF-kB, CREB and AP-1 activation in ∆MEGF11 MDA-MB-231 and 468 cells. This also resulted, in vivo, in a suppression of tumour growth and a decrease in the number of mouse circulating 4T1 breast cancer cells. Surprisingly, overexpression of MEGF11 upregulated the expression of various chemokines and proinflammatory cytokines via AKT activation, but there was no increase in cell proliferation. MEGF11 was found to cross-talk positively with IL-17A signalling. Patients with tumours that over-expressed MEGF11 had a poorer prognosis. We conclude that MEGF11 plays an important role in tumour survival and that overexpression of MEGF11 induces both a cytokine and a chemokine cascade, which will favour the tumour microenvironment in terms of distant metastasis. MEGF11 might be a potential therapeutic target for preventing TNBC recurrence.
Highlights
Our previous study demonstrated that upregulation of multiple epidermal growth factor-like domains 11 (MEGF11) gene expression is involved in the mechanism by which recurrence of Triple Negative Breast Cancer (TNBC) occurs
In addition to the above, Complementary DNA (cDNA) open array analysis of 224 genes using paired TNBC tissue samples (16 recurrent and 24 non-recurrent tissues) showed that MEGF11 was significantly upregulated in tumour tissues from patients where there was subsequent clinical recurrence compared to patients without recurrence
To investigate the critical genes associated with the recurrence of TNBC, we conducted a cDNA open array analysis involving 224 expressed genes using paired TNBC tissue samples (16 recurrent and 24 non-recurrent patients) (Supplementary Information 1) and found that MEGF11 was significantly upregulated in tumour tissue that was associated with subsequent clinical recurrence compared to those without recurrence (Fig. 1a)
Summary
Our previous study demonstrated that upregulation of multiple epidermal growth factor-like domains 11 (MEGF11) gene expression is involved in the mechanism by which recurrence of Triple Negative Breast Cancer (TNBC) occurs. There was a significant decrease in cell growth via inhibition of AKT, NF-kB, CREB and AP-1 activation in ∆MEGF11 MDA-MB-231 and 468 cells This resulted, in vivo, in a suppression of tumour growth and a decrease in the number of mouse circulating 4T1 breast cancer cells. Much effort has been devoted to studying the correlation between the multiple epidermal growth factor-like domain (MEGF) subtypes and their functions. A recent bioinformatics study that targeted the molecular mechanisms present in TNBC tumours demonstrated that several genes were differentially expressed in paired tumour samples when recurrent and non-recurrent patients were compared[25]. The aim of the present study was to elucidate the role of MEGF11 in human TNBC cells, in vitro, in vivo and in human patients
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