APOBEC mutagenesis is a cellular mechanism by which genetic alterations are acquired somatically, driven by APOBEC enzyme family members. This mechanism is prominently observed in 15% of primary and 25% of recurrent breast cancer, the most common cause of cancer-related death in middle-aged women. Current evidence suggests that APOBEC mutagenesis contributes to all disease stages, i.e. cancer initiation, progression and treatment resistance. The core idea of the AMBER project is that unravelling the mechanism of APOBEC mutagenesis induction and maintenance will turn this mechanism into breast cancer’s Achilles heel and yielding therapeutic targets. To prove this, I will answer the following challenging research questions: Why is APOBEC mutagenesis operational in breast cancer? How does APOBEC contribute to disease progression? Can we target tumours having APOBEC mutagenesis specifically?
To this end, I will first collect epidemiological and molecular evidence for factors inducing APOBEC mutagenesis in breast cancer. This may help to prevent APOBEC mutagenesis from occurring, potentially decreasing breast cancer incidence. Second, using global and single cell genomics, I will secure a link between APOBEC mutagenesis and disease progression, giving potential leads to delay progression. Third, I will exploit a likely vulnerability of APOBEC driven breast cancer relying on my finding that these tumours may depend on a proficient homologous DNA repair (HR) pathway. When experimentally confirmed, targeting HR may extinguish APOBEC-driven disease. Finally, and building on my observation that APOBEC mutagenesis associates with a profound immune response, I hypothesize that this is due to the generation of a new class of neo-epitopes being produced. If proven true, targeting these neo-epitopes can provide another effective means to eradicate APOBEC driven tumours by immune therapies. In short, I anticipate that this AMBER project will provide the fundamental insights into APOBEC mutagenesis needed to turn it into an Achilles heel which can be targeted to prevent, delay, and ultimately cure APOBEC-driven breast cancer.
