Reprogrammed oestrogen binding linked to more aggressive breast cancer

Receptors for the female sex hormone oestrogen attach to a different part of the DNA in breast cancer patients who are more likely to relapse, according to a study published in Nature.

Adapted from a news release issued by Cancer Research UK

Wednesday 11 January 2012

Receptors for the female sex hormone oestrogen attach to a different part of the DNA in breast cancer patients who are more likely to relapse, according to a study published in Nature.

The oestrogen receptor (ER) binds oestrogen and regulates the activity of certain genes. The new study found that in more aggressive breast cancers, the oestrogen receptor was being redirected to a different part of the genome by a protein called FOXA1. This suggests that drugs that specifically block FOXA1 could help treat patients who do not respond to conventional hormone treatments, such as tamoxifen.

The study was led by Cancer Research UK’s Cambridge Research Institute in collaboration with a number of other Cancer Research UK-funded scientists and clinicians in the UK including Imperial College London. Dr Carlo Palmieri and Professor Simak Ali, from the Department of Surgery & Cancer at Imperial, also funded by Cancer Research UK and part of the Cancer Research UK Centre at Imperial, provided clinical samples for the study from both primary and importantly secondary breast cancer – tumours from other parts of the body such as the liver as well as cells purified from fluid that collected around the heart in a breast cancer patient. These samples were donated by patients undergoing treatment at Imperial College Healthcare NHS Trust. The College and the Trust are partners in the Academic Health Science Centre, which formed in October 2007 with the aim of improving the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible.

“Most research on breast cancer at the moment is on biopsies from primary tumours,” Dr Palmieri said. “It is harder to obtain samples from secondary tumours but it is really important to study those as well because it tells us about how the disease develops and why it may spread, and could lead to new treatments aimed specifically at breast cancer that has spread to sites outside of the breast.

“We found that ER binds to different parts of the genome in tumours that do well compared with those that relapse and spread. The results suggest that it might be possible to identify cancers that will do poorly based on ER binding. This knowledge will hopefully help us to select which patients need treatment but also in due course the best treatments for individual patients according to the biology of their tumour.”

The researchers used state of the art technology, called ChIP sequencing, to analyse interactions between oestrogen receptors and the genome in frozen breast tumour samples and create a map of all of the sites in the human genome where ER attaches itself to the DNA and switches on particular genes. This map was used to compare where in the genome ER attached in tumours from people that responded well to treatment, compared with those that went on to relapse or were resistant to treatment from the start.

This revealed almost 500 contact points that were common across all the samples analysed, but also a distinct set that were specific to patients with different clinical outcomes – of which 599 were associated with good response to treatment and 1,192 with poor response.

Studying patterns of gene activity in these two areas of the genome allowed the researchers to identify a subset of genes that are more active in tumours that return and spread.

Dr Jason Carroll, who jointly led the study with Professor Carlos Caldas, both at the Cancer Research UK Cambridge Research Institute, said: “These findings suggest that ER binds to different regions of the genome DNA in breast cancer patients that respond to treatment, compared to those that relapse and whose cancer spreads.

“We know from previous studies involving breast cancer cells growing in the lab that a protein called FOXA1 is needed for oestrogen receptors to interact with the DNA and switch on genes that fuel cancer growth. But this is the first time we’ve examined frozen tumour samples and shown that FOXA1 redirects ER to different locations within the DNA in patients with different outcomes. This switches on different sets of genes, which in turn affect the outcome of the patient. We now hope to develop ways of blocking FOXA1 to help treat patients who no longer respond to standard treatments.”