Inhibitor of DNA Binding Proteins in Tumours - Therapeutic Strategies in Cancer Biology and Pathology - page 179

involved with both cell proliferation and survival. Therefore besides downregu-
lating ID4 expression, there are other pathways by which Cdc42 can produce its
phenotypic effects. Equally TNBCs showed far greater ID expression than did non-
TNBCs. ID4 was found in more than 50% of tumour cells in 76/101 TNBCs, whilst
the comparable figure was 6/113 non-TNBCs. Here it is argued that this is due to
the fact that ID4 inhibits and downregulates BRCA1 suppressor (Wen et al., 2012).
ID4 is overexpressed in basal-like breast cancer of which a majority tend to be tri-
ple negative. BRCA1 methylation is not remarkably higher, but mRNA levels were
greatly reduced in cancer than in control, which suggests the possibility of ID4 being
involved in the diminished transcription of BRCA1 (Turner et al., 2007). This postu-
late runs counter to the suppressor function of ID4.
MiRNA-335 has been drawn into the picture and has been implicated in regu-
lating ID4, ERα, IGF1R and Sp1 known to induce BRCA1 expression and by this
means regulate BRCA1. Not only miRNA-335 is downregulated in breast cancer, but
its expression correlated positively with BRCA1. The miRNA upregulates BRCA1
expression (Heyn et al., 2011). This is in agreement with the view that miRNA-335
is an inhibitor of metastasis. Compatibly, miRNA-335 reduces ERα level but when
the endogenous miRNA is suppressed using antisense oligonucleotides, ID4 expres-
sion increases, possibly a compensatory effect indicating a regulatory loop involving
miRNA-335, BRCA1 and ERα. But BRCA1 expression is said to inversely relate to
both ERα and ID4 (Roldan et al., 2006), which insinuates a notion of co-regulatory
link involving the miRNA, BRCA1 and ID4 but not ERα. DAPK1 promoter hyper-
methylation and the presence of miRNA-335 would be expected to be just as effec-
tive in determining potential aggressive behaviour of tumours.
Induction of miRNA-335 in ER− MDA-MB-231 and BT474 breast cancer cells
does indeed inhibit cell migration and metastasis as assayed by the less than ideal
assay of lung colonisation upon tail vein injection even in the absence of ER. This in
fact seems to occur by a different route, namely by inhibiting Sox4, an activator of
EMT (Zhang et al., 2012c). MiRNA-206 also downregulates ERα but not ERβ, pos-
sibly as a result of binding to two sites in the 3′-untranslated region of ERα mRNA
(Adams et al., 2007). Several miRNAs are associated with ER+/node-negative and
one in ER−/node-negative breast cancers and TNBCs (Foekens et al., 2008). The
sheer numerical aspect of miRNA expression is a complicating factor that cannot be
easily addressed whilst setting up experimental protocols (see Table 2.1 and Figures
3.4, 3.5 and 3.6).
Equally, it has been argued not infrequently that ID4 is upregulated in some forms
of cancer, promoted cell proliferation and as discussed below also linked with the
propagation and maintenance of CSCs. As pointed out earlier, ID4 has been seen
to block the suppressors BRCA1 gene transcription in vitro and could downregu-
late its expression in vivo (Wen et al., 2012). Indeed, Ren et al. (2012) regard ID4
as an oncogene, amplified in 32% of high-grade serous ovarian cancers and over-
expressed in most primary ovarian cancers but not in normal ovary. Overexpression
also occurred in a number of tumour cell lines of endometrial cancer, breast cancer
and glioblastoma origin.