The complex relationship between BRCA1 and ERalpha in hereditary breast cancer

Abstract

Breast cancer 1 (BRCA1) was initially identified as one of the genes conferring genetic predisposition to both breast and ovarian cancer. One of the interesting aspects of BRCA1-linked cancers is the observed specificity for estrogen-responsive tissues such as breast and ovary. Recent advances in our understanding of BRCA1-linked breast cancers have revealed a complex relationship between BRCA1 and estrogen receptor alpha (ERalpha) signaling. Estrogen stimulation increases expression of BRCA1 at the mRNA and protein level and conversely BRCA1 functions to both induce ERalpha mRNA expression and act as a negative regulator of ERalpha signaling. Here, we review the relationship between BRCA1 and ERalpha and discuss the use of antiestrogen therapies such as tamoxifen and aromatase inhibitors in the treatment of BRCA1 mutation carriers.

Figure 1

Overview of the regulatory interplay between BRCA1 and ERα. Oestrogen stimulation increases the expression of BRCA1 mRNA levels through mechanism potentially involving both p300 and AhR. BRCA1 in turn regulates ERα at both the mRNA and protein levels. BRCA1 regulates expression of ERα mRNA in an OCT1 dependent manner. In addition BRCA1 can compete with p300 and Cyclin D for binding to ERα and negatively regulate ERα mediated transactivation of its downstream target genes.

Figure 2

BRCA1 mutant carriers retain a single copy of functional BRCA1 and therefore may derive a preventative benefit from some antiestrogen therapies such as aromatase inhibitors. Mutagenic oestrogen metabolites may accelerate loss of the second BRCA1 allele resulting in loss of ERα expression and possible de-differentiation towards a more basal/stem cell like phenotype.