The most common type of breast cancer in older women — estrogen and progesterone receptor (ER/PR) positive breast cancer — has been linked to a protein that fends off aging-related cellular damage. A new study led by Vanderbilt-Ingram Cancer Center researcher David Gius, M.D., Ph.D., now shows how a deficiency in this aging-associated protein may set the stage for these tumors to develop.
The findings, published in Molecular Cell, provide information that could assist in the screening, prevention and treatment of these common age-related cancers. While the young are certainly not spared cancer’s wrath, cancer is primarily a disease of aging, with the majority of cases occurring in people over 50. However, the biological processes that underlie this association are not clear.
“The connection between aging and cancer is one of the most established phenomena in cancer research,” said Gius, associate professor of Cancer Biology, Pediatrics and Radiation Oncology. “The problem to address this clinically significant question is that this field lacks in vivo models to study this.”
In the late-1990s, proteins called “sirtuins” were linked to extended lifespan observed in several species maintained on a calorically restricted diet. These nutrient-sensing sirtuin proteins seemed to defend against aging-related cellular damage. Sirtuins are present in all living organisms, with humans having seven different sirtuin proteins. “When (the sirtuins) were discovered, it seemed obvious to conclude that there might be a mechanistic connection between the genes that determine length of survival and cancer,” Gius said. Previously, while at the National Cancer Institute, Gius and colleagues created mice lacking some of these sirtuins.
They reported last January in Cancer Cell that when they knocked out Sirt3 — a sirtuin localized in the mitochondria, the cellular “power plants” — the mice developed ER/PR positive breast tumors, the most common type of breast cancer in postmenopausal women. These tumors also exhibited increased levels of damaging free radicals and “reactive oxygen species” (ROS) — including superoxide, the primary metabolite of oxygen in the mitochondria — which provided an important clue as to how Sirt3 deficiency might permit these tumors to develop. “The mechanism, at least in part, for why these mice develop receptor positive breast cancer is altered mitochondrial ROS, including superoxide,” Gius said. But how deficiency in a longevity gene led to increased ROS was not clear. Since superoxide is generally removed from the cell with the help of a detoxifying enzyme called manganese superoxide dismutase (MnSOD), Gius hypothesized that the Sirt3 deficiency may abnormally regulate MnSOD.
In the current study, the researchers show that Sirt3 knockout mice have decreased MnSOD activity despite having normal levels of the protein. Gius and colleagues determined that the MnSOD in Sirt3 knockout mice was abnormally modified (with a chemical “acetyl” group) at a specific amino acid (lysine 122). This aberrant modification of MnSOD reduced the enzyme’s ability to detoxify superoxide and appeared to explain the increase in ROS in Sirt3 knockout mouse tumors. “These results suggest that aberrant regulation of MnSOD plays a role in receptor positive breast cancer,” said Gius.
Gius and colleagues also developed an antibody that can assess the acetylation status of MnSOD, which he says can potentially be used “to screen breast tissue samples to determine what women are at risk for (receptor positive) cancer or for recurrence because of this dysregulation of MnSOD.” Additionally, agents that target the acetylation of this amino acid on MnSOD may be useful as chemopreventive therapies in women at risk of these cancers and of recurrence, he noted. The research was supported by grants from the National Cancer Institute and the Department of Defense.
Findings from a new study of 141 adults add to an ongoing medical debate over which patients with symptoms of celiac disease should go on a gluten-free diet. Published in ACS' Journal of Proteome Research, the study concludes that people currently diagnosed as “potential” celiac disease patients and not advised to follow a gluten-free diet may not be “potential” patients at all. Rather, the scientists found that these patients have the same distinctive metabolic fingerprint as patients with full-blown disease who do benefit from gluten-free diets.
In the study, Ivano Bertini and colleagues explain that celiac disease is an autoimmune digestive disorder characterized by the inability to digest a protein called gliadin, a component of gluten, which is found in wheat, rye, and barley. The condition causes diarrhea, bloating, and other symptoms in over 3 million people in the United States alone. Treatment is avoidance of foods containing gluten. But the disease is often undiagnosed or misdiagnosed. Definitive diagnosis involves biopsy of the small intestine, showing tissue damage. People with a positive blood test for the condition but no positive biopsy usually are diagnosed as “potential” celiac patients and may or may not be advised to follow a gluten-free diet.
The scientists used magnetic resonance metabolic profiling to analyze the biochemical markers in the blood and urine of 61 patients with celiac disease, 29 with potential celiac disease, and 51 healthy people. They found that those with potential disease largely shared the same profile as those with the confirmed disease and that the biochemical markers in both groups differed significantly from those of the healthy individuals. “Our results demonstrate that metabolic alterations may precede the development of small intestinal villous atrophy and provide a further rationale for early institution of gluten-free diet in patients with potential celiac disease, as recently suggested by prospective clinical studies,” the scientists conclude.
Smoking accounts for more than a third of cases of the most severe and common form of rheumatoid arthritis, indicates research published online in the Annals of the Rheumatic Diseases. And it accounts for more than half of cases in people who are genetically susceptible to development of the disease, finds the study.
The researchers base their findings on more than 1,200 people with rheumatoid arthritis and 871 people matched for age and sex, but free of the disease. The patients came from 19 health clinics in south and central Sweden, while their healthy peers were randomly selected from the population register. All the participants were aged between 18 and 70. They were quizzed about their smoking habits and grouped into three categories, depending on how long they had smoked. Blood samples were taken to assess all the participants' genetic profile for susceptibility to rheumatoid arthritis and to gauge the severity of their disease, as indicated by their antibody levels.
More than half of those with rheumatoid arthritis (61%) had the most severe form of the disease, which is also the most common form, as judged by testing positive for anticitrullinated protein/peptide antibody (ACPA). Those who were the heaviest smokers – 20 cigarettes a day for at least 20 years – were more than 2.5 times as likely to test positive for ACPA. The risk fell for ex-smokers, the longer they had given up smoking. But among the heaviest smokers, the risk was still relatively high, even after 20 years of not having smoked.
Based on these figures, the researchers calculated that smoking accounted for 35% of ACPA positive cases, and one in five cases of rheumatoid arthritis, overall. Although this risk is not as high as for lung cancer, where smoking accounts for 90% of cases, it is similar to that for coronary artery heart disease, say the authors. Among those with genetic susceptibility to the disease, and who tested positive for ACPA, smoking accounted for more than half the cases (55%). Those who smoked the most had the highest risk.
The authors point out that several other environmental factors may contribute to an increased risk of rheumatoid arthritis, including air pollutants and hormonal factors. But they suggest that their findings are sufficient to prompt those with a family history of rheumatoid arthritis to be advised to give up smoking.
On being asked about why she had decided to write a review, Dr Rayman replied: “There are three main reasons. First, to provide GPs and healthcare professionals with reliable information which could be used in treating patients and setting up healthcare programmes. Second, to raise concern that the levels of selenium are low in the UK and parts of Europe.
Third, to call for further research to clarify the optimal nutritional level with respect to selenium.” Dr Rayman explained that if, for example, there was further research to examine whether selenium as a nutrient could be helpful in slowing the progression of HIV to Aids, then it might provide a low cost solution in African countries particularly affected by HIV. The research so far had been carried out in the United States by Mariana Baum and colleagues of the University of Miami who found that HIV positive individuals have a twenty times greater chance of dying from Aids than those with adequate selenium levels. The Cancer Research Campaign is currently funding a £160,000 pilot study, which started in October 1999 led by Dr Rayman, and involves 500 people in the UK to see whether selenium can provide protection against cancer. This comes after an American study which showed encouraging health benefits for people who increased their daily intake of selenium. Dr Rayman said: “I am currently trying to raise £3.5m in funding to carry out a main UK study involving 10,000 people, when the pilot research finishes at the end of next year. It is essential to get sponsorship as scientific research is the only way to get positive proof of the health benefits of selenium. If a positive effect of selenium on cancer risk were to be established, the Government might then decide to act by adding selenium to the food supply. However, research is also needed to discover the optimal nutritional level with respect to selenium, because if people consume too much then it can become toxic”. Besides Britain, Sweden and Denmark are also taking part in the trial because of low dietary selenium. The US who are also participating in the study, have moderate selenium levels. The difference in countries' selenium levels depends on the amount of selenium present in the soil and which fertilisers are used. Finland has artificially added selenium to its fertilisers since 1984 to raise levels because of the reputed health benefit. In contrast, selenium levels in the UK have declined significantly over the last few decades – probably because we are no longer importing selenium-rich wheat from North America for use in our bread.
The researchers also looked at bone density and structure in the lower leg in around 360 19-year-old men who had previously done sports but had now stopped training. They found that men who had stopped training more than six years ago still had larger and thicker bones in the lower leg than those who had never done sports.
“This result is particularly important, because we know that a bone with a large circumference is more durable and resistant to fractures than a narrower bone,” says Nilsson.
The researchers also studied bone density throughout the body in around 500 randomly selected 75-year-old men. Those who had done competitive sports three or more times a week at some point between the ages of 10 and 30 had higher bone density in several parts of the body than those who had not.
The researchers have therefore established that there is a positive link between exercise while young and bone density and size. The connection is even stronger if account is taken of the type of sports done.
“The bones respond best when you're young, and if you train and load them with your own bodyweight during these years, it has a stimulating effect on their development,” says Nilsson. “This may be important for bone strength much later in life too, so reducing the risk of brittle bones.”