Breast cancer fuelled by mysterious Yin Yang Protein

19 September 2018

An international team of researchers found during their study that tumours can change their ‘appearance’ to evade cancer treatments, using epigenetic mechanisms. The researchers used clinical samples from patients with luminal breast cancer to reveal this. The findings have been published in Nature Medicine.

The team, led by Luca Magnani, from Imperial College in London, is part of the EU H2020 Epipredict consortium. It’s coordinated by Pernette Verschure of the Swammerdam Institute for Life Sciences (SILS) at the UvA. Together they developed strategies to deduce intra-tumour and inter-patient phenotypic heterogeneity.

What are Epigenetic regulatory mechanisms?

Epigenetics is the study of gene expression changes such as switching genes on and off, that does not involve changing the underlying DNA sequence. Epigenetic regulatory mechanisms play an important role in maintaining cell-type specific gene expression. Changes in epigenetic regulation enable cancer tumours to adapt to their environment, evade treatment – and ultimately survive longer.

 

September 2018 Enhancer Nature Medicine figure

Figure showing a linear regression (from the publication in Nature Medicine)

Unique role for Yin Yang protein

In this study, the researchers systemically monitored a specific type of epigenetic regulatory regions, called enhancers. These enhancers act as ciphers to tell the cell to switch on certain genes when they are activated. Chemical modifications of the DNA associated histone proteins were measured in clinical ER+ breast cancer tumours. The results revealed that one particular protein, called Yin Yang 1, has a unique role in driving epigenetic enhancer activity and in switching on a gene called SLC9A3R1.  This specific gene helps cancers grow and evade treatment.

Possible new treatments

The findings regarding Epigenetic tumour evolution open pathways to new treatments. They also help understand why some tumours become resistant to treatment. It suggests that doctors should take new tumour samples when a patient’s cancer spreads around the body.

Luca Magnani explains the value of a second biopsy: 'At the moment, patients usually have a biopsy when they are first diagnosed with breast cancer. Doctors then analyse this tissue sample to identify what type of breast cancer a patient has, as this will dictate the best treatment for them. However, our results suggest tumours switch different genes on and off as they progress, which can fundamentally change their ‘appearance’. Therefore, if a tumour becomes more aggressive, and spreads around the body, we would advise always taking a second biopsy. The cancer might have changed significantly in this time, and would respond to different treatments. Although taking a second biopsy when a patient’s cancer relapses is becoming more common, it’s still not happening all the time.'

Major hurdle for diagnosis and treatment of breast cancer

Breast cancer is the most common cancer type and second most frequent cause of cancer-related death in women. Of all breast cancer patients 70% are diagnosed with estrogen receptor positive (ER+) breast cancer. They receive hormone therapy as follow-up treatment. In more than 20% of the cases, the cancer returns later on and can develop into a more advanced tumour form that metastasizes and spreads around the body.

Intra-tumour and inter-patient phenotypic heterogeneity is a major hurdle for diagnosis and treatment outcome. As said, in this study the researchers tackled tumour heterogeneity by monitoring the epigenome of tumour samples from patients with primary or metastatic ER+ breast cancer.

More teamwork for larger patient sample study

The research team, including researchers from the Department of Surgery and Cancer at Imperial London, the European Institute of Oncology in Milan, the University of Liverpool, and Case Western Reserve University in Cleveland, will now study larger numbers of patient samples. It will follow the same group of patients to track how epigenetic enhancer activation in these cancers evolves.

Investigation of triple negative breast cancer

The team will also investigate a type of breast cancer known as triple negative, which is very difficult to treat. Dr Magnani: 'As expected, our work has raised a lot of questions - and we now need to answer them. But it is only through international collaboration – and working as a team – that we can get this vital work done, and hopefully help more patients beat the disease. We could have never done this on our own.'

The work was funded by the Wellcome Trust, Cancer Research UK and the European Union, EpiPredict (642 691) from the Marie Sklodowska Curie actions programme.

More information

More information on the Epipredict consortium can be found on the Epipredict website

Publication details: Nature Medicine 2018 Sep;24(9):1469-1480. doi: 10.1038/s41591-018-0091-x

Published by  Swammerdam Institute