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.
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.