Biology Reference
In-Depth Information
18
BRMS1 (Breast Cancer Metastasis
Suppressor 1) Gene
BRMS1 is reputedly a metastasis suppresses but does not affect tumorigenicity. It
is downregulated by promoter methylation in breast cancer cell lines and primary
breast cancers and their metastases (Metge et  al., 2008). The conundrum is that
transfection of BRMS1 leads to the development of invasive tumours, but these have
low metastatic potential (Samant et al., 2000). Obviously, one is looking at the inhi-
bition or non-operation of biological events occurring at later stages of metastasis.
We do not know if the tumours formed from implanted transfected cells had induced
angiogenesis, had or had not induced the expression of any angiogenic agents.
Unfortunately, controlling the experiments using empty vector alone does not answer
these questions. Therefore, the suggestion that BRMS1 suppresses metastasis by
atypical means is open to debate even a decade later. As noted below BRMS1 seems
capable of inhibiting CXCR4 and NF-κB signalling. Indeed, indirectly also BRMS1
can achieve this by inducing the expression of ING4 which is capable of inhibiting
angiogenesis via suppression of NF-κB and IL-6 (Li and Li, 2010).
Sin3 are co-repressors that occur in complex with HDACs. These complexes
deacetylate nucleosomes near Sin3-regulated genes to produce repressed chromatin
structure. The BRMS1 protein is a component of the mSin3a HDAC complex and a
repressor of gene transcription. In this way it might be involved in the downregula-
tion of expression of anti-apoptotic genes. Suppression of its expression has led to
increased cell adhesion accompanied by enhanced cell motility in vitro (Sheng et al.,
2012). Inhibition of BRMS1 upregulated CXCR4 and activated NF-κB signalling.
NF-κB notoriously enhances the expression of MMP and uPA and promotes cell
motility. BRMS1 deacetylates the RelA subunit of NF-κB. By suppressing NF-κB, it
is able to inhibit the tumour promoter osteopontin (Samant et al., 2007). Consistent
with this, suppression of endogenous BRMS1 expression in Hep3B cells suppressed
cell apoptosis. Here too BRMS1 seemed to suppress osteopontin expression and pro-
moted apoptosis (Wu et  al., 2012b), which might have occurred via suppression of
NF-κB. As noted before osteopontin functions in conjunction with activated NF-κB
pathways (see Figure 9.1 and Table 9.2). Conversely, NF-κB itself might bring about
the downregulation of BRMS1 expression. RelA/p65 subunit of NF-κB seems to
directly recruit DNMT1 (DNA (cytosine-5)-methyltransferase 1) to methylate and
suppress BRMS1 (Liu et  al., 2012g). But one must add a rider here that NF-κB
transcriptionally activates a vast array of genes such as cytokines (e.g., TNF-α and
interleukins), cell adhesion molecules and functions in conjunction with tumour pro-
moters. This is the first attribution of methylation and downregulation of BRMS1
gene expression, so needs to be explored further.
 
Search WWH ::




Custom Search