BRCA1: a non-genomic ‘brake’ on cancer metabolism

PhD project (3/4 yr research project leading to independent research at the doctorate level)

Claire Perks, Jeff Holly, Nic Timpson


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Rationale

Women with BRCA mutations have a high life-time risk of breast cancer but studies of well defined populations have observed that disease penetrance has increased considerably over time and this increase in risk relates to changes in metabolic status. This is not easily explained by the well-characterised role of BRCA in DNA repair. Another property of BRCA1 has been reported however that would be compatible with these observations. BRCA1 has been shown to bind to and reduce the activity of acetyl coA carboxylase (ACCA), the rate-limiting enzyme in fatty acid synthesis. We have shown that IGF-I-induced growth of breast cancers was dependent upon the upregulation of fatty acid synthase (FASN), the enzyme downstream of ACCA, and this itself was dependent on reducing the association of BRCA1 with ACCA. Mutations in BRCA1 have also been linked to the risk of prostate cancer: fat metabolism is important for the progression of both breast and prostate cancer.

Aims & objectives

An interdisciplinary project investigating the role of BRCA1:ACCA complex formation in fat metabolism and the progression of breast and prostate cancers employing cell models and tumours specimens. In populations the causal effects of genetic variance in the BRCA1/fat metabolism pathway will be examined in relation to the risk and progression of these cancers.

Methods

Formation of the BRCA1:ACCA complex will be examined in a range of breast and prostate cancer cell lines and the UBR60 carcinoma cell line that has been stably-transfected to express BRCA1 in an inducible manner. Cell growth, differentiation status, invasion and migration will be examined using established assays. PCR and western blotting will be used to monitor abundance of mRNA and protein respectively and associations between molecules will be examined using immunoprecipitation. Associations between breast and prostate cancers with genetic variants in BRCA1, its regulators and the fat metabolism pathway will be examined in large cohorts and in data from the UK Biobank.

References


Created on Dec. 16, 2016, 10:47 a.m.

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