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proliferation. But then many genes, besides ERα, that influence tumour growth and
progression would need to be reckoned with. Among them are S100A4, 14-3-3σ and
14-3-3ζ genes. MiRNAs such as miRNA-451 can influence the expression of 14-3-3ζ
as well as EGFR and HER2. There is evidence that EGFR might be involved with
Hippo signalling to modulate cell proliferation (see references provided in relevant
sections).
At the experimental level, there is much credible information about the involve-
ment of p53 in LKB1 function. That LKB1 induced the expression of p21 in a
p53-dependent fashion and led to growth arrest was demonstrated some years ago
(Tiainen et al., 2002). LKB1 has been shown to be functionally linked to the p53/p21
axis and indeed shown to activate the same. LKB1 is said to interact with p53 and
possibly phosphorylate it. LKB1 is targeted to the p21/WAF1 promoter by the medi-
ation of p53 (Zeng and Berger, 2006). Yao et  al. (2008) have identified a p53 and
Sp1 binding site in the LKB1 promoter, which seems to be essential for the func-
tion of p53 as a transcription factor. Inhibition of endogenous LKB1 promotes G1-S
transition together with increase in Rb phosphorylation and this was accompanied by
reduction in p53 and p16 expression (Liang et al., 2010a). Induction of p21 by LKB1
probably can occur also independently of p53 (Setogawa et al., 2006).
LKB1 Suppresses EMT
The significance of the loss of LKB1 in tumorigenesis is dramatically underscored
by the putative attribution to it of the ability to inactivate EMT. Suppression of
LKB1 has had marked effects of enhanced cell motility in lung adenocarcinoma cells
and this was accompanied by activation of EMT by ZEB1 mediation (Roy et  al.,
2010). Using murine bladder epithelia as a model, Shorning et al. (2011) have dem-
onstrated that LKB1 with PTEN, but not individually, suppressed EMT. This seemed
to involve suppression of mTOR signalling. When LKB1 and PTEN were deleted at
the same time, mTOR signalling was upregulated and eventually led to the activation
of EMT and tumorigenesis. As discussed at another location, PI3K/Akt signalling
can and does function through mTOR/Rac and influence both cell proliferation and
migration. However it is unclear how a link between LKB1 and mTOR can be caus-
ally interpreted. Several suppressor proteins are able to suppress mTOR signalling,
KAI and 14-3-3 proteins, for instance. Akt suppresses the function of LKB1 by 14-3-
3ζ mediation. Akt phosphorylates LKB1 at a specific serine residue and promotes
14-3-3ζ binding to the suppressor interfering in this way with its binding to STRAD
and blocking its suppressor function. Inhibition of 4-3-3ζ using specific siRNAs pro-
moted translocation of LKB1 from the nucleus to the cytoplasm (Liu et al., 2012b).
On the other hand, it has been shown that 14-3-3ζ prevents LKB1 from phosphoryl-
ating its AMPK substrate and this effectively inhibits the suppressor effects of LKB1
(Bai et al., 2012).
MiRNAs might be another candidate that have to be reckoned with. Many miR-
NAs, Let-7d, miRNA-34c, miRNA-194 and miRNA-200c, inhibit EMT (see
pp. 18-21). Therefore is it is of some interest to note here that activation of EMT by
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