Elucidating the novel BRCA1 function as a Non-Genomic metabolic restraint in ER-positive breast cancer cell lines

Moses O Koobotse, Jeff M. P. Holly, Claire Perks*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)
246 Downloads (Pure)

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-á (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.

Original languageEnglish
Pages (from-to)33562-33576
Number of pages15
JournalOncotarget
Volume9
Issue number71
DOIs
Publication statusPublished - 11 Sep 2018

Structured keywords

  • ICEP

Keywords

  • BRCA1
  • IGF-I
  • cancer
  • p-ACCA
  • non-genomic

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