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correlated in breast cancer samples. ERα seems able to inhibit LKB1 in breast can-
cer cells. Oestradiol inhibits LKB1 expression, and siRNA-mediated suppression of
ERα upregulates LKB1 transcription. ER binds to the LKB1 promoter on which sev-
eral oestrogen response elements have been detected (Brown et al., 2011; Linher-
Melville et al., 2012). So one would expect ERα would positively correlate with
EGFR. Nonetheless any postulated relationship between LKB1 and EGFR is indeed
not robust. The lack of strong evidence of concomitant genetic changes in LKB1 and
EGFR may also be interpreted in this way and suggest they may be suppressed as
parallel events but independently of each other. One has to exercise some caution in
interpreting the effects involving ERα or indeed ERα and ERβ.
In murine and human adipocytes, 17β-oestradiol/ERα upregulated LKB1 tran-
scription and phosphorylation of AMPK, but androgens produced an opposite effect
(McInnes et al., 2012). However, so far as breast cancer cell lines are concerned,
oestradiol reduces the expression of LKB1. 5-Aminoimidazole-4-carboxamide
1-d-ribonucleoside (AICAR)-mediated activation of AMPK exerts anti-proliferative
effects on breast cancer cell lines MCF-7, MDA-MB-231 and T47D, but the degree
of responses differed considerably. T47D (ER+/mutant p53+) were most sensitive
to the effects of AICAR and MCF-7 (ER+/wild-type p53+) and MDA-MB-231
(ER−/mutant p53+) are the least sensitive. Of these T47D showed cell cycle arrest
but other two cell lines showed induction of apoptosis. As discussed previously,
AMPK activation has been attributed to the activation of p53 and p21, but here in
MDA-MB-231, the apoptotic effect seems to occur independently of p53. In MCF-7
cells apoptosis is not known to be dependent upon p53 and probably also the case
upon AICAR treatment. But a comparison between T47D and MDA-MB-231 would
suggest ER expression might be relevant to the inhibition of cell growth. Phenformin
(a biguanide related to metformin) also exerted similar effects with the same sensitiv-
ity pattern (El-Masry et al., 2012). However, the situation is more complex than one
can imagine. For instance, metformin suppresses HER2 (Vazques-Martin et al., 2012).
MDA-MB-231 cells do indeed overexpress HER2, so the effects noticed might have
occurred independently of ER expression.
Nath-Sain and Marignani (2009) showed previously that binding occurred
between LKB1 and ERα in the nucleus and suggested that LKB1 is thus targeted to
ER-responsive genes. More debatably, LKB1 transactivated ERα, which is incongru-
ous with the propensity of tumour promotion with ERα. But in the event, it is pos-
sible to take the view that ERα and LKB1 could form a mutually regulatory loop. A
potential outcome could be alteration of the balance of the tumour-promoting ERα
and inhibitory ERβ. It has become apparent from studies concerning the suppressor
effects of nm23-H1 and nm23-H2 isoforms that ERα and ERβ can outweigh each
other's effects on promotion of cell growth and migration. The phenotypic outcome
can be a consequence of the function of the equilibrium between ERα and ERβ being
tilted in favour of either receptor.
It is needless to say that this would remain in the realm of speculation until we
know if LKB1 exerts any effects on ERβ. Nonetheless, one would not fail to notice
that there is a fundamental contradiction here and therefore any suggestions of a
therapeutic spin off would be premature. Oestrogens function via ERα to induce
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