APOBEC Mutagenesis: a novel Achilles heel of Breast cancer

Introduction

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 APOBEC mutagenesis contributes to all disease stages, i.e., cancer initiation, progression, and treatment resistance.

Project Overview

The core idea of the AMBER project is that unraveling the mechanism of APOBEC mutagenesis induction and maintenance will turn this mechanism into breast cancer’s Achilles heel. To prove this, I will answer several challenging research questions:

1. Why is APOBEC mutagenesis operational in breast cancer?
2. How does APOBEC contribute to disease progression?
3. Can we target APOBEC mutagenesis or APOBEC-driven tumors specifically?

Research Objectives

Epidemiological and Molecular Evidence

First, I will reveal 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.

Link to Disease Progression

Second, using global and single-cell genomics, I will secure a link between APOBEC mutagenesis and disease progression, giving leads to delay progression.

Targeting Vulnerabilities

Third, I will exploit a potential vulnerability of APOBEC-driven breast cancer, since I have found that these tumors may depend on a proficient homologous DNA repair (HR) pathway. When experimentally confirmed, targeting HR may extinguish APOBEC-driven disease.

Immune Response and Neo-epitopes

Finally, I have observed that APOBEC mutagenesis associates with a profound immune response. I hypothesize that this is due to a new type of neo-epitopes being produced. If proven true, targeting these neo-epitopes provides another effective means to eradicate APOBEC-driven tumors.

Conclusion

I am confident AMBER will provide the fundamental insights into APOBEC mutagenesis needed to turn it into an Achilles heel which may help to prevent, delay, or cure APOBEC-driven breast cancer.