Biology Reference
In-Depth Information
17
The BRCA1 and BRCA2
Suppressor Genes
The development and systemic spread of breast cancer are closely allied to the
loss of BRCA1 and BRCA2 suppressor genes. BRCA1 and BRCA2 are described
as breast cancer susceptibility genes in that familial breast/ovarian cancer are a
consequence of a germ line mutation in one of the alleles and a subsequent loss of
function mutation in the second allele. BRCA1 has been associated with cell differ-
entiation and embryonic development. Somatic mutations have been encountered in
breast and ovarian cancers. The predisposition to develop cancer is related to muta-
tions and the abrogation of suppressor function of the gene. Inactivation of these
suppressor genes enhances cell proliferation and tumour growth, and mutations in
these genes correlate to a high degree with inactivation of p53. The wild-type genes
function as negative regulators of cell proliferation and tumour growth, and these
abilities are bound to impinge upon and influence tumour progression. BRCA1
shows reduced expression in association with transition of in situ breast cancer to
the invasive phase. Loss of heterozygosity of both BRCA1 and BRCA2 is more fre-
quent in metastatic tumour than in primary breast carcinoma. The BRCA1 protein is
a zinc-finger protein and therefore might participate in the regulation of gene tran-
scription. Germ line mutations of BRCA1 seem to result in total loss of transcrip-
tion or lead to the production of a truncated product, which might be functionally
impaired (Sherbet, 2003).
BRCA1 and BRCA2 proteins have been attributed with putative participation in
DNA repair. They participate in homologous recombination DSBR (double strand
break repair). The defect in this process arising from genetic changes makes carriers
of BRCA gene mutations more sensitive to radiation damage. It has been known for
some time that BRCA2+/+ but not BRCA−/− cells can survive radiation damage.
It would appear from recent studies that miRNAs play a role in radiation sensitivity.
Moskwa et  al. (2011) found that inhibition of miRNA-182 not only raised BRCA1
protein levels but also provided protection from effects of ionising radiation. They
also state that sensitivity to radiation results from impairment of homologous recom-
bination repair which accompanies downregulation of BRCA1 protein and enhanced
miRNA-182 expression. Chang et  al. (2011c) have offered an alternative mode of
action. They show that BRCA1 can interact with HDAC2 leading to the deacetyla-
tion of histones H2A and H3 on the promoter of the miRNA and in this way repress
the oncogenic miRNA-155 and inhibit cell proliferation.
The BRCA1 suppressor function has ramification with another miRNA. MiRNA-
335 seems able to regulate ERα, ID4, IGF1R and Sp1. 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
 
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