Decoding epigenetic adaptation to adjuvant endocrine therapies in hormone-dependent breast cancer
File(s)
Author(s)
Sanchez Cabanillas, Claudia
Type
Thesis
Abstract
Hormone-dependent Breast cancer (HDBC) is the most common cancer type in women. Adjuvant endocrine therapies (ET) disable oestrogen-mediated tumour growth, and they have helped many patients become cancer-free. However, in up to 40% of cases the disease returns, sometimes decades later. This phenomenon stems from cancer cells that can disseminate early from the primary tumour and survive by entering a prolonged life-suspended state called dormancy. Dormant cells can avoid detection and treatment. At an unknown future timepoint, they can awaken and resume proliferation with resistant traits. Understanding the adaptive evolutionary mechanisms behind dormancy entry and exit has become critical to effectively treat HDBC. Instead of defined genetic mutations, previous work in our lab uncovered epigenetic changes specific to dormancy that could explain ET adaptation: a set of repressive histone modifications – H3K27me3, H3K9me2 and H4K20me3 – that decorate DNA in repressive areas of chromatin and contribute to its structure within the nucleus.
This thesis interrogates the epigenomic landscape formed by this set of modifications. First by generating genome-wide histone enrichment maps across the main ET adaptation stages in a lineage-traced, long-term oestrogen-deprivation experiment mimicking ET in vitro. These profiles generated by CUT&Tag, revealed histone-specific patterns of deposition with context-specific consequences in transcription; and together they show dormancy is a convergent but reversible cell state that reprogrammes multiple potential sources of adaptive mechanisms, marking genes of oestrogen receptor (ER) signalling, and developmental pathways. Further generation and analysis of parallel regulatory datasets showed histone remodelling also occurs at DNA damage domains, ER binding sites, and open chromatin regions. Lastly, I investigated three-dimensional chromatin reorganisation associated with dormancy, by imaging H4K20me3-marked domains at the super-resolution scale (STORM), and by profiling all DNA-DNA contacts (HiC), both of which revealed significant structural rewiring. Together this work contributes towards identifying potential adaptive vulnerabilities in ET-induced dormancy.
This thesis interrogates the epigenomic landscape formed by this set of modifications. First by generating genome-wide histone enrichment maps across the main ET adaptation stages in a lineage-traced, long-term oestrogen-deprivation experiment mimicking ET in vitro. These profiles generated by CUT&Tag, revealed histone-specific patterns of deposition with context-specific consequences in transcription; and together they show dormancy is a convergent but reversible cell state that reprogrammes multiple potential sources of adaptive mechanisms, marking genes of oestrogen receptor (ER) signalling, and developmental pathways. Further generation and analysis of parallel regulatory datasets showed histone remodelling also occurs at DNA damage domains, ER binding sites, and open chromatin regions. Lastly, I investigated three-dimensional chromatin reorganisation associated with dormancy, by imaging H4K20me3-marked domains at the super-resolution scale (STORM), and by profiling all DNA-DNA contacts (HiC), both of which revealed significant structural rewiring. Together this work contributes towards identifying potential adaptive vulnerabilities in ET-induced dormancy.
Version
Open Access
Date Issued
2025-10-03
Date Awarded
01/02/2026
License URL
Advisor
Magnani, Luca
Di Antonio, Marco
Sponsor
Medical Research Council (Great Britain)
Publisher Department
Department of Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)