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

A malignancy-risk gene signature developed for breast cancer has been found to have predictive and prognostic value for patients with early stage non-small cell lung cancer. The advancement was made by researchers at Moffitt Cancer Center in Tampa.
According to corresponding author Dung-Tsa Chen, Ph.D., associate member with the Moffitt Biostatistics program, non-small cell lung cancer (NSCLC) accounts for 80-90 percent of all lung cancers. Patients with NSCLC have a 30-50 percent relapse rate after surgery and a 40-70 percent five-year survival rate. Although adjuvant chemotherapy (ACT) has increased survival rates and has become standard treatment for NSCLC, a proportion of patients do not derive any benefit from it.
‘Better prognostic tools have been needed to identify both patients with a high probability of relapse and those who would benefit from adjuvant chemotherapy,’ said Chen.
He added that the Moffitt researchers are confident that their newly tested malignancy-risk gene signature for NSCLC will provide that tool because their malignancy-risk gene signature is a proliferative gene signature, one associated with both cancer risk and progression.
According to the researchers, their findings suggest a ‘transferability’ of the malignancy-risk gene signature between breast cancer and NSCLC, a ‘unique feature not seen in other gene signatures derived for various tumor types.’
‘To the best of our knowledge, our study is the first to show a high consistency of the gene signature on both breast cancer and NSCLC,’ said Chen. ‘The gene signature demonstrated a statistically significant association with overall survival and other clinical predictors in NSCLC.’
Originally, the malignancy-risk signature gene was designed to distinguish between normal breast tissues and breast cancer tissues by identifying abnormal molecular structure. The Moffitt research team further applied the signature to tissue samples from 442 NSCLC patients in the Director’s Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma.
‘Additionally, the malignancy-risk gene signature has demonstrated the potential to identify early-stage NSCLC patients who would be likely to benefit from adjuvant chemotherapy,’ explained Chen. ‘This malignancy-risk gene signature may provide an additional tool to help identify a subset of patients at high-risk for low overall survival and who may benefit from ACT.’
Study results revealed a predictive feature of the malignancy-risk gene signature with an ability to predict overall survival in NSCLC patients. Further, the malignancy-risk gene signature was able to consistently distinguish between low and high malignancy risk groups and correlate the groups by good to poor overall survival rates. Moffitt Cancer Center

Atrial fibrillation, or irregular heartbeat, is a very common heart rhythm disturbance that increases the risk of stroke and death. It is usually treated with warfarin, where the dose is calculated by measuring the coagulation of the blood. The dose is increased if coagulation is too quick, and decreased if it is too slow. Patients with unsatisfactory samples are tested more frequently, while satisfactory samples mean that the test interval can be extended.
Researchers at the Sahlgrenska Academy at the University of Gothenburg and Chalmers University of Technology in Sweden have now devised a new method that improves the accuracy of risk assessment. In a study involving 20,000 patients in Sweden, a new measurement method was tested that assesses far more reliably who is at risk of serious complications and admission to hospital. The method takes into account how blood viscosity fluctuates and also takes account of the values’ extremes to establish far more reliably which patients are at risk of a stroke, haemorrhage or death. The new method improves the chances of understanding which patients are at risk of complications, and is therefore an indicator for stepping up checks and probably reducing the risks. It also helps in the decision to discontinue warfarin in favour of other drugs in at-risk patients.

Binding Site, the Birmingham-based healthcare manufacturer, develops and produces laboratory-based tests for the diagnosis and monitoring of blood cancers and immunodeficiency diseases. The company recently won the EEF Midlands Outstanding Export Award, sponsored by UK Trade and Investment (UKTI), and will go on to compete in the National Awards final in January. The annual awards are hosted by EEF, the manufacturers’ organisation, and recognise excellence in enterprise, innovation, environmental performance and skills development among UK manufacturers.
Binding Site’s export strategy has been developed and refined for more than ten years to become integral to all aspects of the business. Initially, the export initiative was led by the sales and marketing team, but as overseas expansion gathered pace, the company drew on the support of technical, R&D, HR and finance departments.As a result of this highly successful multi-disciplinary approach, Binding Site currently exports around 90% of its products, with the United States accounting for 47% of total sales. The judging panel, led by Cranfield University, praised Binding Site’s achievements, stating that it was extremely impressed by the challenging target market featured in the story, the United States. Despite tough regulations, Binding Site had broken through and was now experiencing progressive growth.