Scientists based at the Cancer Research UK Cambridge Research Institute have discovered how 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.
Crucially, they also found that within these more aggressive breast cancers, the oestrogen receptor (ER) was being ‘redirected’ to a different part of the genome by a protein called FOXA1. So drugs that specifically block FOXA1 could help treat patients who do not respond to conventional hormone treatments, such as tamoxifen.
The researchers used state of the art technology, called ChIP sequencing, to analyse ER-genome interactions 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, versus 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 of contact points 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.
Carlos Caldas, Professor of Cancer Medicine at the Department of Oncology at the University of Cambridge and the Cancer Research UK Cambridge Research Institute said: ‘Some breast cancers are treated with hormone treatments, such as tamoxifen, which work by blocking oestrogen receptors. But we know that about a third of patients either fail to respond to this type of treatment or go on to relapse at a later date.
‘Understanding the genetic differences that determine who will or won’t respond to a given treatment is a vital step in being able to choose the right drugs for individual patients. The next step will be to see if these findings can be repeated in larger groups of patients.’
Cancer Research UK’s Dr Jason Carroll, who jointly led the study with Professor Caldas, 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.’ University of Cambridge

Fibroblasts, cells that play a role in the structural framework of tissues, play an apparent role in melanoma tumour growth. Fibroblasts also contribute to melanoma drug resistance and may also facilitate the ‘flare’ response when a tumour’s metabolism is enhanced following a patient being removed from a targeted therapy, said researchers at Moffitt Cancer Center in Tampa.
Alexander R. Anderson, Ph.D., co-director of Integrative Mathematical Oncology at Moffitt, and Moffitt Comprehensive Melanoma Research Center member Keiran S. Smalley, Ph.D., along with colleagues from the Wistar Institute in Philadelphia, investigated the role of fibroblasts in melanoma progression.
‘A role for fibroblasts in cancer progression has long been suspected,’ explained Anderson, who works with mathematical models of cancer to investigate tumour cell- microenvironment interactions. ‘In this study, we used an integrated mathematical and experimental approach to investigate whether melanoma cells recruit, activate and stimulate fibroblasts to deposit certain proteins known to be pro-survival for melanoma cells.’
Fibroblasts are the most common of connective tissues, and they function to synthesise the ‘extra cellular matrix’ of cells and collagen, the structural framework – also called ‘stroma’ – for tissues.
The researchers knew that fibroblasts were drawn to cancer cells and that they became activated by cancer cells. They also knew that different cancer cell lines have varying capabilities for recruiting and stimulating fibroblasts. An expectation has been that aggressive cancers stimulate fibroblasts more than do less aggressive cancers.
When they investigated the relationship between fibroblasts and tumours using mathematical models, the research team came up with some unexpected findings.
Anderson and Smalley expected the fibroblast-derived ‘extra cellular matrix’ that supports the tumour structure to have ‘direct effects on tumour behaviour.’ However, once they ran their theoretical models they came up with a number of unexpected conclusions with potentially far-reaching implications about drug resistance and tumour growth.
‘Our finding that the fibroblast population might facilitate the ‘flare response’ – a period during which a tumour has enhanced metabolism and increases it progression trajectory after patients are removed from targeted therapy – was a surprise,’ said Smalley, whose research aims at developing new therapies for melanoma and getting them into clinical practice.
The researchers knew that a targeted therapy would kill only the tumour population, not the fibroblasts in the tumour structure. However, the finding that fibroblasts contribute to melanoma drug resistance was unexpected.
‘Targeted therapies may actually hasten tumour progression when they are stopped due to resistance to the targeted drug,’ said Smalley. ‘We found in our models that fibroblasts appear to facilitate the flare response after targeted therapy ends.’
Their conclusions about the relationship between fibroblasts and cancer tumours were not predicted or expected, but revealed though the use of mathematical models.
‘If these conclusions are confirmed experimentally, we may gain important new insights into how drug resistance can be managed clinically,’ concluded Anderson. H. Lee Moffitt Cancer Center & Research Institute