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modulate cytoskeletal dynamics; this possibly explains the inhibition of invasion by
nm23 which is also known to target the cytoskeletal machinery.
Deployment of MPA as an anti-metastatic and anti-angiogenic agent is being
clinically evaluated in postmenopausal patients with ER−/PR− breast cancer and
in locally recurrent and metastatic breast cancer in combination with cyclophospha-
mide plus methotrexate (NCT00577122). Treatment of endometriod adenocarci-
noma by MPA is also being studied (NCT00064025); its effect as a chemopreventive
agent (NCT00003179) is also being assessed. Another phase III study is looking into
how effective MPA might be in preventing endometrial disorder in postmenopausal
women with ductal carcinoma
in situ
, lobular carcinoma
in situ
, Paget's disease, and
stage I or stage II breast cancer and who are on tamoxifen therapy (NCT00002920).
Targeting S100A4 to Restore nm23 Function
In the framework of upregulating nm23 expression, targeting S100A4 and in this way
enabling nm23 function would appear to provide a novel therapeutic approach. This
has exceptional relevance in tumours types which significantly display an inverse
relationship between the expression of nm23 and S100A4 and EGFR and ER/PR.
Although this has not been examined thoroughly at present, currently available evi-
dence indicates that nm23+ tumour cell lines tend to be EGFR− and ER/PR+, whilst
in contrast S100A4+ ones are more often than not EGFR+ and ER/PR−. That EGFR,
nm23 and S100A4 might be co-ordinately regulated is supported by the demonstration
sometime ago by Parker and Sherbet (1992) that verapamil downregulated S100A4
in B16 murine melanoma cells and not in the opposite direction as incorrectly stated
elsewhere (Sherbet, 2011a). Verapamil significantly reduced EGFR expression at both
the mRNA and protein levels in A549 cells and also significantly enhanced the expres-
sion of nm23 protein, but nm23mRNA remained unchanged suggesting that here
the effect was exerted at the translation level or later (Zhang et al., 2009a). Recently
nm23-H2 has been found to negatively regulate EGF- and Ras-induced activation of
the ERK pathway and cellular proliferation (Lee et al., 2009). This situation is fully
compatible with the findings of Lin et al. (2002) who reported that oestrogen induced
the expression of nm23-H1 mRNA and protein and that this corresponded with levels
of ERα. Furthermore, ER antagonists inhibited nm23-H1 transcription.
An area of vibrant interest covers TNBCs. TNBCs are most refractory to treat-
ment by their very nature of being ER−/PR−/HER2− and therefore show no
response to tamoxifen, aromatase inhibitors or to Herceptin. Around a tenth of breast
cancers turn out to be triple negative, TNBCs are highly aggressive and associated
with enhanced recurrence and metastasis and poor prognosis. Thus the problem of
managing these patients is a seriously tactical proposition. The relationship that
seems to subsist between S100A4/nm23 and ER/EGFR (possibly also HER2, not
established todate) might lend itself to further exploration of potential approach to
inhibit S100A4 as a means of upregulating nm23 in TNBCs.
Promoter methylation has often been seen as a route to silencing gene expres-
sion. SiRNA are able to target genes that possess sequence homology with siRNAs
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