̽��ֱ�� of Cambridge - National Health and Medical Research Council of Australia

Breast cancer genetic variants found to alter how cells respond to oestrogen

cjb250 — Mon, 29 Feb 2016 16:52:02 +0000

Breast cancer is the most common type of cancer among women. Around one in eight women in the general population is expected to develop the disease at some point in her life. ̽��ֱ��majority of cases occur in women aged 50 and over.

̽��ֱ��female sex hormone oestrogen acts as a trigger, binding to a molecule known as an oestrogen receptor in most breast cells and triggering a cascade of signals that cause the cell to behave normally. However, the oestrogen receptor is switched off in some cells and these do not respond to the hormone.

An international collaboration, led by researchers at the ̽��ֱ�� of Cambridge and the QIMR Berghofer Medical Research Institute, examined the DNA surrounding the gene for the oestrogen receptor – known as ESR1 – in women with different types of breast cancer against those of healthy controls to identify genetic variants responsible for an increased risk of breast cancer. ̽��ֱ��results are published today in the journal Nature Genetics.

Among their findings, the researchers discovered five cancer-risk variants based within or around the ESR1 gene. This gene has long been known to be related to the risk and progress of breast cancer, but little is understood of how it works and why it should affect breast cancer.

Of the five variants discovered by the team, four were more strongly associated with tumours where the ESR1 gene is switched off, so the tumour cells have no oestrogen receptors. These represent around one fifth of breast cancers.

One of these four variants was of particular interest as it was associated with a rarer type of breast tumour that contain active receptors for the protein known as ‘human epidermal growth factor 2’ (HER2). Such tumours can be treated by the drug trastuzumab (marketed as Herceptin). This is believed to be the first time a specific genetic risk factor for HER2 positive breast tumours has been found.

Dr Stacey Edwards’ team from QIMR Berghofer, Brisbane, had been searching for gene regulatory elements around the ESR1 gene, which act like the volume controls on a radio or TV, turning the activity of the nearby genes up or down. There are two major types of gene regulators: ‘enhancers’, which increase activity of the genes express such that they make more protein, and ‘silencers’, which have the opposite effect.

When the Cambridge and Brisbane teams compared notes, they spotted that four of the breast cancer risk variants coincided with ‘volume-up’ enhancers. These particular regulators did not just affect the ESR1 gene but also other nearby genes. ̽��ֱ��variants that increased risk of breast cancer directly reduced the effectiveness of each enhancer, hence turning down the volume of ESR1 and the other nearby genes. This reduced the amount of oestrogen receptor produced by breast cells.

̽��ֱ��researchers say that their results suggest the ESR1 gene works with other nearby genes to affect breast cancer development.

̽��ֱ��fifth genetic variant was found to be more strongly associated with tumours where the oestrogen receptor is switched on. This variant coincides with and alters the effectiveness of ‘volume-down’ silencer, which means that it increases the amount of oestrogen receptor protein produced by breast cells.

“It’s interesting that all five of the genetic variants that we have found affect levels of oestrogen receptors in breast cells,” says Dr Alison Dunning from the Department of Oncology at the ̽��ֱ�� of Cambridge, one of the lead authors on the study. “This suggests that there may be a ‘Goldilocks’ level of these receptors in breast cells: too few or too many and the breast cells are more likely to become cancerous.”

“As our research looks at how tumours with and without the oestrogen receptor are regulated, it’s possible it could help make sense of the enduring mystery of how tamoxifen works and why tumours develop in these two divergent ways,” says Dr Edwards, one of the study’s senior authors. “Our findings could open the way to developing new, more specific breast cancer preventions.”

̽��ֱ��genetic variants are all very common, each one carried by around one in three women. Each variant only increases the risk of developing breast cancer by a small amount.

Professor Doug Easton, another senior author from the ̽��ֱ�� of Cambridge, adds: “breast cancer is a very complex disease, with many genes, and other factors, contributing to an overall increased risk of developing the disease. These five common variants that we have identified will contribute to an eventual predictive test for breast cancer risk, and for determining the risk of the particular subtype of breast cancer, that will include hundreds of similar variants.”

Funding for the study came from organisations including the European Union, Cancer Research UK, the National Health and Medical Research Council of Australia and the Australian National Breast Cancer Foundation.

Dr Alan Worsley, Cancer Research UK’s senior science information officer, said: “We know that hundreds of genes are likely to play a role in how cancers start. And this latest study adds more detail to our genetic map of breast cancer risk, potentially helping understand which type of breast cancer is likely to develop based on a woman’s genetic makeup. Understanding more about each individual’s risk of cancer could help us find ways to potentially prevent the disease or pick it up in its earliest stages."

Reference
Dunning, AM et al. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1. RMND1 and CCDC170. Nature Genetics; published online 29 Feb 2016. DOI: 10.1038/ng.3521.

An international study of almost 120,000 women has newly identified five genetic variants affecting risk of breast cancer, all of which are believed to influence how breast cells respond to the female sex hormone oestrogen.

There may be a ‘Goldilocks’ level of oestrogen receptors in breast cells: too few or too many and the breast cells are more likely to become cancerous

Alison Dunning

williami5

Breast cancer reflection

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At the edge of vision: Struggling to make sense of our cluttered world

cjb250 — Wed, 25 Nov 2015 17:00:00 +0000

Even with 20/20 vision in broad daylight on a clear day, our peripheral vision can be surprisingly poor, particularly when the scene in front of us is cluttered. Now, scientists at the ̽��ֱ�� of Cambridge, UK, Northeastern ̽��ֱ��, Boston, USA, and Queensland Brain Institute, Brisbane, Australia, believe they are a step closer to understanding why this is.

“When objects in our peripheral vision are surrounded by visual clutter, a phenomenon known as ‘visual crowding’ hinders our ability to make sense of what we see,” explains Dr Will Harrison from the ̽��ֱ�� of Cambridge. “Visual crowding is ubiquitous in natural scenes and affects virtually all everyday tasks, including reading, driving and interacting with the environment. But this failure of vision isn’t a problem with our eyes – it represents a processing limit of the brain.”

Image: Focus on the green spot. Without moving your eyes, you should be able to identify the letter ‘A’ on the left side of the display; the same letter is almost impossible to see on the right side of the display.

In a study published today in the journal Current Biology, Dr Harrison and Professor Peter Bex from Northeastern ̽��ֱ�� have shed new light on how constraints in the brain limit our peripheral vision.

̽��ֱ��researchers showed volunteers a series of images with differing levels of visual crowding. To make sure they kept their eyes still, the volunteers were asked to focus on a dot. Beside the dot was a broken ring, like the letter ‘C’, but with the gap positioned at a random orientation. ̽��ֱ��volunteers were asked to estimate the angle at which the gap appeared by freely rotating a second C so that it matched the target as closely as possible. This helped the researchers to measure each individual’s uncrowded perceptual acuity.

To measure crowded perception in the next stage, the C was surrounded by an additional, larger C – a ‘distractor’ – at different orientations and/or distances to the target C. ̽��ֱ��volunteers again rotated a second C until they thought it matched the target. Whereas previous studies looking at crowding had only given binary results – was the observer right or wrong? – this new method enabled the researchers to quantify crowding as a continuous experience.

̽��ֱ��researchers found that when the angle of the target and distractor were similar, observers tended to choose an average of the two orientations. When the target and distractor angles were quite different, observers tended to choose either the correct orientation (that of the target) or they mistakenly reported the orientation of the distractor. However, this effect depended on the target and distractor being positioned very closely together – reports were not influenced by a distractor positioned a large distance away from the target.

Combining the findings with a computational model of how visual neurons represent the visual field, Dr Harrison and Professor Bex found that problems in identifying objects in our peripheral vision are due primarily to a combination of two factors. First, in a crowded scene, our visual resolution is degraded, meaning that we become less precise at locating an object’s detail. Second, we confuse which detail belongs to which object, to the extent that part of one object can appear ‘swapped’ with a part of a different object. Importantly, their model suggests that both factors are caused by the same underlying brain mechanism.

Dr Harrison believes the findings may have implications for quantifying and treating vision disorders, such as age-related macular degeneration (AMD). A large portion of the elderly population suffers from AMD, which causes debilitating central blindness. ̽��ֱ��loss of high-resolution central vision forces AMD sufferers to rely solely on peripheral vision, which is very poor due to visual crowding.

“We hope that in future it may be possible to adapt our methods to quantify the degree to which patients with AMD are visually-impaired,” explains Dr Harrison. “At the moment, it can be difficult to quantify the extent or severity of their visual deficits. Our method would allow a careful examination of the function of AMD patients’ remaining vision, which could in turn lead to better rehabilitation techniques down the track.”

̽��ֱ��research was funded by the National Institutes of Health, USA, and the National Health and Medical Research Council of Australia.

Reference
William J Harrison and Peter J Bex. A unifying model of orientation crowding in peripheral vision. Current Biology; 25 Nov 2015

As you’re driving to work along a busy road, your eyes on the traffic lights ahead, hoping they won’t turn to red, you pass signs warning of roadworks, ads on bus shelters… Suddenly a dog runs out in front of you. What are your chances of seeing it before it’s too late?

When objects in our peripheral vision are surrounded by visual clutter, a phenomenon known as ‘visual crowding’ hinders our ability to make sense of what we see

Will Harrison

Sam Saunders

Advisory Cycle Lanes and Pavements Being Abused On Parry's Lane (cropped)

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