Up to 40% of patients treated for oestrogen-receptor positive breast cancer (ERBC) relapse with resistant tumours. Studies failed to identify driver mutations of relapse in at least 60% of patients, so I investigated the underlying genetic and epigenetic mechanisms.
I analysed mutational signatures throughout ERBC evolution. Using published primary and metastatic cohorts, we showed that patients can be stratified based on mutational signatures. Using novel patient and in vitro datasets, we found that mutational signatures play a significant role in ERBC: APOBEC SBS2 and SBS13 are enriched at enhancers, clock-like SBS5 is enriched at expressed regions, and SBS2 is associated with top ERBC driver PIK3CA. We also showed that mutational signatures are context dependent, as they are shaped by genomic location, cellular lineage, endocrine therapy, and microenvironment. Last, we provided clues towards the aetiology of SBS2, SBS13 and SBS5.
I analysed drivers of resistance to endocrine treatment. In a large-scale in vitro whole genome sequencing experiment, I failed to find recurrent mutations among known ERBC coding and non-coding drivers, while in a targeted sequencing analysis of two other cohorts I also failed to find novel coding drivers.
I investigated the mechanism of Yin-Yang 1 (YY1) recruitment to chromatin. YY1 transcription factor is a major player in ER+ breast cancer biology, found at bona fide enhancers. We tested a model for YY1 binding to chromatin: a stimulus such as oestradiol induces changes in histone modifications, that in a combinatorial mode recruit YY1, which leads to chromatin remodelling mediated by its interactors. We found that YY1 is not inducible, while data on its recruitment by the histone code is more difficult to disentangle. SILAC nucleosome affinity purification revealed that YY1 binds to a combination of H3K and H4K acetylation, while loss of H4K16ac did not lead to loss of YY1 binding.