Abstract
Within populations carrying the same genetic predisposition, the penetrance of BRCA1 mutations has increased over time. Although linked to changes in lifestyle factors associated with energy metabolism, these observations cannot be explained by the established role of BRCA1 in DNA repair alone.We manipulated BRCA1 expression using tetracycline in the UBR60-bcl2 cell line (which has an inducible, tetracycline-regulated BRCA1 expression) and siRNA in oestrogen receptor(ER)-positive MCF7 and T47D breast cancer cells. Cellular responses to BRCA1 silencing and IGF-I actions were investigated using western blotting, 3-H Thymidine incorporation assay, cell fractionation and co-immunoprecipitation.We demonstrated that the loss of BRCA1 resulted in downregulation of a phosphorylated and inactive form of acetyl CoA Carboxylase-α (ACCA), with a concomitant increase in fatty acid synthase (FASN) abundance. BRCA1 was predominantly cytoplasmic in ER-positive breast cancer cells, compatible with the observation that BRCA1 physically associates with phosphorylated ACCA, which is a cytoplasmic protein. We also found that IGF-I induced de-phosphorylation of ACCA by reducing the interaction between BRCA1 and phosphorylated ACCA. BRCA1 deficiency enhanced the non-genomic effects of IGF-I, as well as the proliferative responses of cells to IGF-I.We characterized a novel, non-genomic role for BRCA1 in restraining metabolic activity and IGF-I anabolic actions.
Highlights
The breast cancer 1, early onset (BRCA1) gene is frequently mutated in familial breast cancers and women harbouring these germline mutations have an increased risk of developing breast cancer [1, 2]
We report that BRCA1 is predominantly localised to the cytoplasm in estrogen receptor (ER)+ breast cancer cells where it associates with p-Acetyl CoA carboxylase-α (ACCA) (S79)
Using UBR60-bcl2 cell line with an inducible, tetracyclineregulated BRCA1 expression described previously [25], we show that BRCA1 induction resulted in an increase in ACCA phosphorylation (Figure 1A)
Summary
The breast cancer 1, early onset (BRCA1) gene is frequently mutated in familial breast cancers and women harbouring these germline mutations have an increased risk of developing breast cancer [1, 2]. The BRCA1 gene product has established roles in the maintainance of genome integrity [6,7,8], the increasing penetrance of BRCA1 mutations over time within populations carrying the same genetic predisposition [2, 9] suggests that BRCA1 may be involved in other roles beyond the genome. Acetyl CoA carboxylase exists as ACCA and acetyl CoA carboxylase-ß (ACCB) isoforms, with ACCA involved in de novo fatty acid synthesis in the cytosol whereas ACCB regulates mitochondrial fatty acid oxidation on the outer mitochondrial membrane [13]. In the fatty acid synthesis pathway, ACCA catalyses the rate-limiting step of the pathway and generates substrates for fatty acid synthase (FASN) [14]. Phosphorylation of a number of serine residues has been shown to regulate www.oncotarget.com
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