Guertin lab has a new publication on ANKLE1 in cancer.

03-01-23. The Guertin lab characterized the normal physiological role of the protein ANKLE1 in red blood cell development and how increased expression of Ankle1 leads to an increased risk of developing breast cancer.

Background: GWAS analyses have identified thousands of regions associated with physiological phenotypes and disease risk phenotypes. Integrative GWAS and eQTL analyses can often hone in on the candidate causal genes within the region by looking for colocalization of GWAS and eQTL variants. The genotyping revolution allows geneticists to keep identifying more associated loci with smaller and smaller effect sizes, but characterizing the causal genes and mechanisms by which the genes manifest as organismal phenotypes lags substantially behind. The chr19p13.1 locus was first identified over 10 years ago as a locus that contributes to the risk of breast and ovarian cancer. The wrong genes were thought to be the causal genes for over six years, but integration with eQTL analysis repeatedly and convincingly pointed to ANKLE1 as the causal gene. There are only a handful of rigorous publications that have explored the molecular, cellular, and physiological functions of ANKLE1, but none of these studies explore the role of ANKLE1 in breast cancer biology. ANKLE1 is primarily expressed in hematopoietic tissues of vertebrates, but ANKLE1-deficient mice are viable without any detectable phenotype in hematopoiesis.

This latest work finds that the developmental role of ANKLE1 is to cleave the mitochondrial genome during erythropoiesis. Drs. Przanowski and Guertin also determined how ectopic expression of ANKLE1 confers breast cancer risk. The publication in Communications Biology reports that ectopic expression of ANKLE1 in breast epithelial spheroids cleaves mitochondrial DNA to induce mitophagy and trigger a shift in metabolism to glycolysis. These metabolic changes cause resistance to apoptosis in TP53 negative cells. Two recent GWASs quantified mitochondria DNA abundance and found that genetic variants with the ANKLE1 locus contribute to mitochondrial DNA abundance. This publication provides a direct mechanistic link between the overlapping GWAS signal for breast cancer risk and mitochondrial DNA copy number.

This entry was posted in News.