Inhibitor of DNA Binding Proteins in Tumours - Therapeutic Strategies in Cancer Biology and Pathology - page 177

Is ID4 a Tumour Suppressor?
A large body of evidence has built up supporting the tumour suppressor function of
IDs. ID4 is downregulated in many tumours but not without exceptions. The loss of
expression is occasioned by epigenetic modification. So ID4 is deemed a tumour
suppressor protein. The gene is silent in a vast majority of AML and CLL patients,
and its association with DAPK1 (death-associated protein kinase 1) in CLL has
underscored the relevance of ID4 in the pathogenesis of CLL. DAPK is involved
in apoptosis and autophagy and its loss of expression occurs in many tumours. It
may be recalled that DAPK1 shows epigenetic modulation and reduced expression
in sporadic CLL (Raval et al., 2007). Hypermethylation has been linked with meta-
static spread (Martinez-Glez, 2007). In fact, AML and CML differed in respect of
frequency of methylation of ID4, SFRP1 and SHP1, methylation being higher in
AML patients than CML patients. But the suppressor gene DLC1 and cadherin,
among others, displayed no differences (Uhm et al., 2009). This possibly indicates
sharing of functions between ID4 and different suppressor entities in AML and
CML and could relate to the characteristics of the acute and chronic conditions.
Myelodysplastic syndrome (MDS) which carries a 1/3 risk of transformation into
AML has shown ID4 promoter methylation. Frequency of methylation was higher in
advanced MDS subtypes and in the higher risk groups assessed by the international
prognostic scoring system. Also ID4 methylation correlated with poor prognosis and
reflected more rapid progression in patients with ID4 methylation as compared with
those without methylation (Wang et al., 2010a).
The frequency of methylation and the degree of methylation are the criteria for
defining the state of methylation and sometimes implied or interpreted as equivalent
measures. The extent or degree of methylation is of overriding importance for it is
suggestive of more aggressive disease and correlated in prostate cancer with tumour
grade and reflected potential earlier recurrence (Sharma et al., 2012; Vinarskaja
et al., 2012). Umetani et al. (2005) reported some time ago that ID4 methylation
was found in 16/24 node-positive and 7/36 node-negative T1 primary breast cancers.
Another study has also drawn attention to the frequent loss of ID4 expression by pro-
moter methylation in 117/170 of primary breast cancers. ID4 promoter methylation
reflected poor prognosis in terms of recurrence-free survival and further it was asso-
ciated with tumour spread to the regional lymph nodes. ID4 loss did not correlate
with tumour size, grade or ER/PR status (Noetzel et al., 2008). This is intriguing.
But the authors had made no attempt to look at the expression of cell proliferation
markers. Furthermore, inclusion of ductal carcinomas in situ (DCIS) of different
grades would have shown whether ID4 loss affected the invasive process. But ear-
lier, de Candia et al. (2006) noted a striking inverse relationship between ER and
ID4 expression in normal breast epithelia. Virtually all DCIS and invasive carcino-
mas that showed downregulation of ID4 mRNA were ER+ and 3/31 ID4+ invasive
carcinomas were ER−. A point to be stressed here is that the debate might be incon-
clusive when attribution is restricted to global ER rather than ERα and ERβ, which
have divergent biological effects.