Investing molecular mechanisms that link DNA repair deficiency and immune response in triple negative breast cancer

Breast cancer is the most frequent malignancy in women. Improved clinical management and targeted therapeutics have dramatically improved patient outcome in the disease. But not for all patients.

For roughly 10% of women with breast cancer there are still limited treatment options as their tumors are negative for current treatment predictive markers (so called triple negative breast cancer, TNBC), representing a clinical challenge.

TNBC is characterized by DNA repair deficiency and highly scrambled genomes, inflicting (likely) a, paradoxically, prognostically favourable immune response in some but far from all patients. In this proposal we aim to understand why.

Through profiling of early stage TNBC by state of the art genome-wide methods at the DNA, epigenetic, RNA, and protein levels coupled with spatial in situ expression methods and in vitro / in vivo experiments we will shed more light on the interplay between tumor associated DNA repair deficiency and immune response in the tumor microenvironment: the two key prognostic and treatment predictive markers in TNBC.

We expect that this combined approach of clinical data and functional assays will provide a roadmap for TNBC tumor stratification and reveal mechanisms whereby tumors with ongoing similar genome-wide tumorigenic processes elicit different immune response.

Understanding the latter is clinically important with the introduction of immunotherapy and may aid in better risk stratification and treatment prediction.