Uncovering the Secrets of the Breast Cancer Epigenome
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The epigenome plays a crucial role in the development of breast cancer. This exciting and rapidly evolving area of research holds great promise for new interventions – from prevention through to personalized treatment.
“Epigenetics has many definitions, but the one we like is mechanisms that regulate transmissible phenotypes that are not directly driven by changes in the sequences of protein-coding genes,” says Luca Magnani, Senior Research Fellow at Imperial College London.
Epigenetic features include DNA methylation, histone modifications, non-coding RNAs and chromatin structure. We now know that epigenetic dysfunction is a central feature of many cancers, including breast cancer, but there are still large gaps in our knowledge about its effects.
“It’s a major hole in our understanding of how cancer’s work,” says Duncan Sproul, Cancer Research UK Career Development Fellow at the University of Edinburgh.
Increasing our understanding about epigenetics and breast cancer could open a wealth of potential new applications for prevention, diagnosis and treatment.
Epigenetics in cell biology
Epigenetics is thought to play a role in multiple fundamental processes within cells. One of the most well-studied is how the epigenome influences gene expression, which has such a crucial role in cell identity and plasticity during development – and consequences for the phenotype of cancer cells.
“Epigenetic features are likely to say how easy or hard it is for a transcription factor to get access to a regulatory sequence to turn a gene on or off,” says Sproul.
However, a fundamental question remains unresolved – that of causality.
“Although there’s a pretty good correlation between some epigenetic marks and the gene activity state, it’s hard to conclusively say that these modifications are driving the change in transcription,” explains Magnani.
The cancer epigenome
More than three decades ago, researchers first identified that tumor cell DNA was hypomethylated compared to normal cells.
“With new technologies, we can now see exactly which parts of the genome lose this methylation,” says Sproul. “But we still don’t understand what’s causing it – and that really precludes us from asking what role it plays in cancer.”
We now know that many cancers have gross alterations to their epigenetic profile. But the significance of what this epigenomic reorganization means for the initiation and development of the disease remains elusive.
“It’s assumed that these changes help promote cancer, but we don’t actually know that for certain,” says Sproul.
The most prevalent hypothesis is that epigenetic modifications lead to perturbed gene expression patterns – affecting key genes involved in cancer.
“For example, there’s pretty good evidence that BRCA1 acquires DNA methylation in its promoter in some tumors – and that this correlates with the gene being turned off,” says Sproul.
Supporting the hypothesis that DNA methylation leads to gene silencing, researchers recently identified a 5’ UTR variant associated with epigenetic silencing of the BRCA1 tumor suppressor gene due to promoter hypermethylation in two families affected by early-onset breast and ovarian cancer.
“This is the closest we’ve come to a true “epigenetic cause” of breast cancer, so it was quite an exciting report,” says Sproul.
From diagnosis to treatment
Epigenetic changes offer new opportunities for improving the diagnosis of breast cancer. For instance, there is plenty of excitement around their potential application in liquid biopsies, circumventing the need for an invasive tissue biopsy.
“We can see, for example, DNA methylation in cell-free DNA,” says Sproul. “So it’s possible that you might be able to detect epigenetic changes using a blood test.”
This approach may offer the opportunity to improve both the early detection of the disease – as well as gain insight into the molecular subtype of breast cancer at the time of diagnosis, helping to guide treatment decisions.
There is also the promise of new drugs that can target aberrant epigenetic pathways – some already approved for treating some cancers, especially leukemia. Although none are yet available for breast cancer, some are showing promising results in preclinical studies – such as inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers.
Tackling drug resistance
Targeting epigenetic modifications could also help to overcome drug resistance in breast cancer. “While estrogen-positive tumors are usually treated with hormone therapies, around one-third of women will relapse,” says Magnani.
The dogma was that when the tumor comes back, the resistance to hormone therapies would be explained by new genetic mutations. But evidence from in vitro studies instead suggests that it may actually emerge from epigenetic reprogramming.
“The caveat is that we’re taking breast cancer cells from one patient and growing them in a dish, which obviously eliminates some of the things that make a tumor a tumor,” qualifies Magnani.
However, recent studies carried out directly on patient tumor tissues are also showing similar results. For instance, a preliminary study of HER2-positive cancers suggests that epigenetic differences may influence tumor response to the targeted therapy, trastuzumab.
The hope is that understanding how the epigenome contributes to drug resistance will uncover new biomarkers that can help predict the timing or likelihood of relapse – as well as translate into new interventions to attack drug-resistant tumors.
“The cool thing about epigenetics is that it’s reversible,” says Magnani. “So if we understand what’s driving drug resistance, then these modifications could potentially be targeted.”
Recent advances in technologies, such as chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq), are enabling large-scale epigenetic mapping.
“We are now able to profile the entire epigenome of a cancer,” says Sproul.
The International Human Epigenetic Consortium (IHEC) is coordinating the generation of epigenomic reference data from primary cells and tissues. Other large collaborations include Encode, which is building a comprehensive parts list of functional elements in the human genome – and Blueprint that aims to decipher at least 1,000 epigenomes from healthy and cancerous blood cells.
“But these big consortia are more limited in scope to those that have been carried out for straight genomics,” says Magnani. Individual laboratories are also carrying out epigenomic analyses of tumor samples, albeit at a smaller scale.
“My group has now profiled about 50 breast cancers,” says Magnani. “We’ve even got the technology to work on metastatic biopsies where tissues are very limited.”
Single cell technologies
There are also exciting opportunities to analyze the epigenome at a single cell level.
“There are protocols to do single cell epigenomics – but currently these are only for cell lines,” says Magnani. “But it’s just a question of time before we can bring these to clinical samples.”
The next stage will be to pair ChIP-seq with single-cell transcriptomics, which will enable researchers to explore the fundamental question of whether epigenetic modifications can switch a gene on or off. And there is even the potential to use these technologies on individual tumor cells on pathology slides in situ.
“That would really be very powerful for understanding the organization of cancers that have epigenetic heterogeneity,” says Sproul.
Modifying the epigenome to prevent cancer
Epigenetics may even help explain the association between breast cancer risk and increasing age, with a recent study linking DNA methylation-based measures of a woman’s biological age with her chance of developing the disease.
This opens tantalizing future opportunities around breast cancer prevention, as it may be possible to modify these epigenetic modifications through diet and lifestyle interventions – reducing a person’s risk.
“Epigenetics is something very dynamic and so the idea of reversibility through convincing people to implement better habits could have a dramatic impact on cancer incidence,” says Magnani.