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inhibits these processes, albeit by different signalling systems and ligand dependent
or independent manner (Lazennec et al., 2001; Sanchez et al., 2010). But 17β-HSD1
(17beta-hydroxysteroid dehydrogenase type 1), which is involved in oestradiol syn-
thesis and activation of dihydrotestosterone, enhanced the levels of both ERα and
ERβ and promoted cell growth and migration. ERα levels had increased to a far
greater extent than did ERβ (Aka et al., 2012). Obviously here promotion of cell
growth and migration by ERα might have prevailed against the negative effects of
ERβ. Hence, the relationship between oestrogen/ER and progesterone with invasive
behaviour is not quite as straightforward as it would appear.
Sometime ago Lin et al. (2002) found that oestrogen induced the expression of
nm23-H1mRNA and protein and this corresponded with levels of ERα. Also these
effects were accompanied by suppression of invasive behaviour
in vitro
. The media-
tion of ERα was evident from the fact that BCM1 cells lacking the receptor showed
no response to oestrogen. Antagonists of oestrogen inhibited nm23-H1 transcription.
According to Sahab et al. (2010), ER− cells derived from breast cancer also show a
marked reduction in nm23-H1. Therefore, in the environment of nm23-H1, it is essen-
tial to note that it interacts with and increases the engagement of ERα with ERE and
suppress transcription of oestrogen-responsive genes such as cathepsin D and Bcl-2.
Inhibition of nm23-H1 by using siRNA enhanced the expression of these genes gen-
erating its suppressor effect (Curtis et al., 2007). Compatible are also the findings of
Rayner et al. (2008) who most convincingly demonstrated that nm23-H2 co-localised
with ERβ but not with ERα. In MCF-7 cells over expressing ERβ, nm23-H2 nearly
doubled ERE related transcription. Furthermore, oestrogen and nm23-H2 synergisti-
cally reduced cell migration
in vitro
, obviously an ERβ-mediated effect. Also relevant
in relation to cancer is that similar co-ordinated expression is found in vascular cells
associated with atherosclerosis and inflammation (Rayner et al., 2007).
Also there is much circumstantial and inferential evidence that the nm23-H1 pro-
moter responds to corticosteroids and hence the suggestion that steroids could be
deployed to activate nm23 function. In fact dexamethasone does induce increase of
nm23-H1 expression and this increase is glucocorticoid receptor dependent (Ouatas
et al., 2003).The perceived differences might be due to the fact that the two ERs
differ in biological function and also one is dealing here with two different nm23
proteins. Nm23-H2 is identical in sequence to PuF (the Purine binding factor), an
activator of c-myc and also implicated in the activation of several genes involved in
myeloid differentiation, whilst it is uncertain if nm23-H1 has transcriptional func-
tions. A function ascribed to nm23-H1 is monitoring the integrity of DNA repair and
replication. So by and large the two proteins could be influenced differently by oes-
trogen and might differentially impact disease prognosis.
Manipulation of nm23 Expression as a Therapeutic Approach
Gene therapy can be administered in many ways. Where the appropriate path is
silencing of genes as in the case of tumour and metastasis promoter genes, suppres-
sion of gene expression by methylation of the promoter of the genes, inhibition of
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