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.
Breast cancer patients who have a strong social support system in the first year after diagnosis are less likely to die or have a recurrence of cancer, according to new research from investigators at Vanderbilt-Ingram Cancer Center and the Shanghai Institute of Preventive Medicine. The study, led by first author Meira Epplein, Ph.D., assistant professor of Medicine, was published in a recent edition of the Journal of Clinical Oncology.
Patients in the study were enrolled in the Shanghai Breast Cancer Survivor Study, a large, population-based review of female breast cancer survivors in China, which Vanderbilt University Medical Center and the Shanghai Institute of Preventive Medicine have carried out since 2002 under the leadership of principal investigator Xiao Ou Shu, M.D., Ph.D., professor of Medicine, and senior author of the study.
From 2002 to 2004, a total of 2,230 breast cancer survivors completed a quality of life survey six months after diagnosis and a majority responded to a follow-up survey 36 months postdiagnosis. The women were asked about physical issues like sleep, eating, pain, psychological well-being, social support and material well-being. The answers were converted to an overall quality of life score. During a median follow-up of 4.8 years after the quality of life assessment, the investigators documented participants who had died or been diagnosed with a cancer recurrence.
Six months after diagnosis, only greater social well-being was significantly associated with a decreased risk of dying or having a cancer recurrence. Compared to women with the lowest scores, women who scored highest on the social well-being quality of life scale had a 48 percent reduction in their risk of a cancer recurrence and a 38 percent reduction in the risk of death.
Among the facets that comprise the social well-being domain, emotional support was the strongest predictor of cancer recurrence. Specifically, women reporting the highest satisfaction with marriage and family had a 43 percent risk reduction, while those with strong social support had a 40 percent risk reduction and those with favorable interpersonal relationships had a 35 percent risk reduction.
“We found that social well-being in the first year after cancer diagnosis is an important prognostic factor for breast cancer recurrence or death,” said Epplein. “This suggests that the opportunity exists for the design of treatment interventions to maintain or enhance social support soon after diagnosis to improve disease outcomes.” While a strong social support network influenced cancer recurrence and mortality during the first year, the association tapered off and was no longer statistically significant by the third year after diagnosis.
This may be related to a smaller sample size of patients who answered the questionnaire, or other factors beyond quality of life that take precedence in the later years of survival. The study was supported by grants from the U.S. Department of Defense Breast Cancer Research Program and the National Cancer Institute.
New findings from the Monell Center reveal that weight gain of formula-fed infants is influenced by the type of formula the infant is consuming. The findings have implications related to the infant’s risk for the development of obesity, diabetes and other diseases later in life. “Events early in life have long-term consequences on health and one of the most significant influences is early growth rate,” said study lead author Julie Mennella, Ph.D., a developmental psychobiologist at Monell. “We already know that formula-fed babies gain more weight than breast-fed babies. But we didn’t know whether this was true for all types of formula.”
While most infant formulas are cow’s milk-based, other choices include soy-based and protein hydrolysate-based formulas. Protein hydrolysate formulas contain pre-digested proteins and typically are fed to infants who cannot tolerate the intact proteins in other formulas. In adults, pre-digested proteins are believed to act in the intestine to initiate the end of a meal, thus leading to smaller meals and intake of fewer calories. Based on this, the authors hypothesized that infants who were feeding protein hydrolysate formulas would eat less and have an altered growth pattern relative to infants feeding cow’s milk-based formula.
In the study, published online in the journal Pediatrics, infants whose parents had already decided to bottle-feed were randomly assigned at two weeks of age to feed either a cow’s milk-based formula (35 infants) or a protein hydrolysate formula (24 infants) for seven months. Both formulas contained the same amount of calories, but the hydrolysate formula had more protein, including greater amounts of small peptides and free amino acids. Infants were weighed once each month in the laboratory, where they also were videotaped consuming a meal of the assigned formula. The meal continued until the infant signaled that s/he was full.
Over the seven months of the study, the protein hydrolysate infants gained weight at a slower rate than infants fed cow milk formula. Linear growth, or length, did not differ between the two groups, demonstrating that the differences in growth were specifically attributable to weight. “All formulas are not alike,” said Mennella. “These two formulas have the same amount of calories, but differ considerably in terms of how they influence infant growth.”
When the data were compared to national norms for breast-fed infants, the rate of weight gain of protein hydrolysate infants was comparable to the breast milk standards; in contrast, infants fed cow’s milk formula gained weight at a greater rate than the same breast milk standards. Analysis of the laboratory meal revealed the infants fed the protein hydrolysate formula consumed less formula during the meal. “One of the reasons the protein hydrolysate infants had similar growth patterns to breast-fed infants, who are the gold standard, is that they consumed less formula during a feed as compared to infants fed cow’s milk formula” said Mennella. “The next question to ask is: Why do infants on cow’s milk formula overfeed?”
The findings highlight the need to understand the long-term influences of infant formula composition on feeding behavior, growth, and metabolic health. Future studies will utilize measures of energy metabolism and expenditure to examine how the individual formulas influence growth, and how each differs from breastfeeding. Also contributing to the study, which was funded by the National Institute of Child Health and Human Development, were Monell scientists Gary Beauchamp and Alison Ventura.
More than half of women with breast cancer have low vitamin D levels, British researchers report.”Women with breast cancer should be tested for vitamin D levels and offered supplements, if necessary,” says researcher Sonia Li, MD, of the Mount Vernon Cancer Centre in Middlesex, England. The findings were presented at the San Antonio Breast Cancer Symposium.
Some studies have suggested a link between low vitamin levels and breast cancer risk and progression, but others have not, she says. No studies have proven cause and effect. Previous research suggests a biologic rationale for vitamin D putting the brakes on breast cancer development and spread, Li says. Breast cancer cells have vitamin D receptors, and when these receptors are activated by vitamin D, it triggers a series of molecular changes that can slow cell growth and cause cells to die, she says. Even if it does not have a direct effect on the tumor, vitamin D is needed to maintain the bone health of women with breast cancer, Li says. That's especially important given the increasing use of aromatase inhibitors, which carry an increased risk of bone fractures, she says.
Vitamin D is found in some foods, especially milk and fortified cereals, and is made by the body after exposure to sunlight. It is necessary for bone health.
For the study, Li and colleagues collected blood samples from 166 women with breast cancer and measured their levels of vitamin D. Of the total, 46% had vitamin D insufficiency, defined as levels between 12.5 and 50 nanomoles per liter (nmol/L) of blood. Another 6% had vitamin D deficiency, with levels lower than 12.5 nmol/L. When ethnicity was considered, vitamin D levels were lower in Asian women than in white or other women: an average of about 36 nmol/L vs. 61 nmol/L and 39 nmol/L, respectively.
The researchers theorized that vitamin D levels would be higher in the summer, when there are more daylight hours, but the study showed no association between vitamin D levels and seasons. Last month, the U.S. Institute of Medicine issued updated guidelines stating that a blood level of 50 nmol/L (or 20 nanograms/milliliter) is sufficient for 97% of people.
This study was presented at a medical conference. The findings should be considered preliminary as they have not yet undergone the “peer review” process, in which outside experts scrutinize the data prior to publication in a medical journal.
The pilot study used four women, all of whom were breast cancer survivors, and monitored changes in their blood of key molecules involved in the growth of cancer cells. The participants were asked to fast on the day of the tests and had blood samples taken before and after eating a portion of watercress. The scientists found that six hours after they had eaten the leaves, the women experienced a drop in the activity of a molecule called 4E binding protein, which is thought to be involved in helping cancer cells survive.
Laboratory studies also showed that extracts taken from watercress leaves inhibited the growth of breast cancer cells. The findings build on epidemiological studies that have shown people who eat watercress and other vegetables rich in isothiocyanates, such as broccoli and cabbage, are at lower risk of developing cancer.
Hazel Nunn, Cancer Research UK's health information manager, said the current study was too small to draw any firm conclusions.
She added: “Watercress may well have benefits but there's no reason to believe that it should be superior to a generally healthy, balanced diet that is high in fibre, vegetables and fruit and low in red and processed meat, salt, saturated fat and alcohol.”
Researchers have long speculated that the diet may help explain why nations in the Mediterranean region have historically had lower rates of heart disease and some cancers, including breast cancer, compared with other European countries and the U.S.
Until now, only two other studies have looked at the relationship between Mediterranean-style eating and the risk of breast cancer, both done in the U.S. Each found a connection between the diet and lower breast cancer risk, although in one the link was limited to breast cancers that lack receptors for the hormone estrogen — which account for about one-quarter of breast tumors.
The current study focused on women in Greece, as it is the “cradle” of the Mediterranean diet, and a large segment of the population still adheres to it, Dr. Dimitrios Trichopoulos, the senior researcher on the work, told Reuters Health by email.
At the outset, the study participants completed detailed dietary questionnaires and gave information on their lifestyle habits and demographics. Each woman was given a Mediterranean diet score, ranging from 0 to 9, based on how often they consumed vegetables, legumes, fruit and nuts, whole grains, fish and olive oil or other sources of monounsaturated fats; they also won points by limiting meat and dairy.
Of the 14,800 women included, 240 were diagnosed with breast cancer over an average follow-up of 10 years.
Overall, postmenopausal women whose Mediterranean diet scores were in the 6-to-9 range were 22 percent less likely to develop breast cancer than their counterparts with scores between 0 and 3. That was with factors such as age, education, smoking history, weight and exercise habits taken into account.
The findings show an association between Mediterranean eating and lower breast cancer risk, but do not prove cause-and-effect, according to Trichopoulos, who is with the Harvard School of Public Health in Boston and the Bureau of Epidemiologic Research at the Academy of Athens in Greece.
Further studies are needed to confirm the results, he said.
However, other evidence suggests ways the Mediterranean diet might curb cancer risk.
Research has found, for instance, that women who closely follow the diet tend to have lower levels of estrogen, which fuels the growth of the majority of breast cancers, than other women do. Other studies in the lab suggest that the fats found in the Mediterranean diet — both olive oil and the omega-3 fats in oily fish — may slow the growth of cancer cells.
The diet is also typically rich in antioxidants, which protect body cells from damage that can eventually lead to disease, including cancer. Trichopoulos said that if the Mediterranean diet does have a protective effect against cancer, it is “likely” to involve that antioxidant component.
It also makes sense, said the researcher, that the diet could affect the risk of postmenopausal, but not premenopausal, breast cancer.
Younger women who develop breast cancer, he explained, often have a genetic vulnerability to the disease, whereas in older women, lifestyle and environmental exposures may be relatively more important contributors to risk.
Based on their findings, Trichopoulos and his colleagues write, the association between the Mediterranean diet and breast cancer is of “modest, but not negligible, strength.”
In the U.S., a woman's chance of being diagnosed with breast cancer rises from about a half a percent, or one in 233, during her 30s, to about four percent, or one in 27, during her 60s.
Established risk factors for breast cancer include older age and having had a first-degree relative diagnosed with the disease. Research has also linked obesity, sedentary lifestyle, use of hormone replacement therapy and high alcohol intake to an increased risk.
SOURCE: Journal of Clinical Nutrition
“It may be that the amount of omega-3 fatty acids in fish oil supplements are higher than most people would typically get from their diet,” White said.
However, White cautioned against gleaning any recommendations from the results of one study.
“Without confirming studies specifically addressing this,” she said, “we should not draw any conclusions about a causal relationship.”
Edward Giovannucci, M.D., Sc.D., professor of nutrition and epidemiology at the Harvard School of Public Health and an editorial board member of Cancer Epidemiology, Biomarkers & Prevention, agreed.
“It is very rare that a single study should be used to make a broad recommendation,” said Giovannucci. “Over a period of time, as the studies confirm each other, we can start to make recommendations.”
Still, fish oil continues to excite many, as evidence emerges about its protective effect on cardiovascular disease and now cancer.
Harvard researchers are currently enrolling patients for the randomized Vitamin D and Omega-3 Trial (also called VITAL), which will assess the impact of fish oil supplements and vitamin D on cancer, heart disease and stroke.
The researchers plan to enroll 20,000 U.S. men aged 60 years and older and women aged 65 years and older who do not have a history of these diseases and have never taken supplements.
In most women folate, a type of B vitamin, reduces the risk of breast cancer. However, in women with a certain genetic make-up it has shown to be the opposite: folate raises the risk of breast cancer.
“Therefore I think it is too soon to introduce a general fortification of foodstuffs with folic acid”, says nutrition researcher Ulrika Ericson of Lund University.
Neither does she think it is a good idea to take multivitamin tablets and other dietary supplements containing folic acid (the synthetic form of folate) without special reason.
“It is better to eat a diet containing a lot of fruit, vegetables, legumes and wholemeal products. Then you get sufficient quantities of the natural form of folate, other vitamins and dietary fibre.”
In her doctoral thesis, Ulrika Ericson has taken as her starting point the major study from the 1990s, Malmö Diet and Cancer, which gathered information and blood samples from over 17 000 women. At the end of 2004, just over 500 of these women had developed breast cancer. Folate levels, genetic make-up and food habits in the breast cancer patients have then been compared with the corresponding data from the healthy women.
Those women whose intake of folate corresponded to the level recommended in Sweden had only half as great a risk of getting breast cancer as those who had the lowest intake of folate. This was the overall finding, which shows that folate generally protects against breast cancer. However, the breast cancer risk increased in line with folate levels for a specific sub-group among the women – those who had inherited a certain variant of an enzyme that affects how folate is used in the body.
The ten per cent of the women who had inherited this variant from both of their parents had the highest risk of breast cancer, particularly if they also took vitamin tablets containing folic acid.
“No-one knows which genetic variant of this enzyme they have. This is why I think people should only take dietary supplements if there is a particular reason to do so, not just because 'it's probably a good idea'”, says Ulrika Ericson.
She considers that there are two groups who could have a particular reason to take a folic acid supplement. These are people with a certain type of anaemia and low folate levels and women who are trying to become pregnant (folate reduces the risk of neural tube defects in babies).
To be on the safe side, others should avoid vitamin tablets containing folic acid while it is still unclear what the link is between folate and different types of cancer. Mandatory folic acid fortification of foodstuffs, which has been discussed in many countries including Sweden, is not appropriate in the current situation, according to Ulrika Ericson.
The scientists looked for three nucleotides in breast milk (adenosine, guanosine and uridine), which excite or relax the central nervous system, promoting restfulness and sleep, and observed how these varied throughout a 24-hour period.
“You wouldn't give anyone a coffee at night, and the same is true of milk – it has day-specific ingredients that stimulate activity in the infant, and other night-time components that help the baby to rest”, explains Sánchez.
The benefits of breast milk
The World Health Organisation (WHO) says breast milk is the best food for the newborn, and should not be substituted, since it meets all the child's physiological requirements during the first six months of life. It not only protects the baby against many illnesses such as colds, diarrhoea and sudden infant death syndrome, but can also prevent future diseases such as asthma, allergies and obesity, and promotes intellectual development.
The benefits of breastfeeding also extend to the mother. Women who breastfeed lose the weight gained during pregnancy more quickly, and it also helps prevent against anaemia, high blood pressure and postnatal depression. Osteoporosis and breast cancer are also less common among women who breastfeed their children.
Current chemotherapies do not work against cancer stem cells, which is why cancer recurs and spreads. Researchers believe that eliminating the cancer stem cells is key to controlling cancer.
In the current study, researchers took mice with breast cancer and injected varying concentrations of sulforaphane from the broccoli extract. Researchers then used several established methods to assess the number of cancer stem cells in the tumors. These measures showed a marked decrease in the cancer stem cell population after treatment with sulforaphane, with little effect on the normal cells. Further, cancer cells from mice treated with sulforaphane were unable to generate new tumors. The researchers then tested sulforaphane on human breast cancer cell cultures in the lab, finding similar decreases in the cancer stem cells.
“This research suggests a potential new treatment that could be combined with other compounds to target breast cancer stem cells. Developing treatments that effectively target the cancer stem cell population is essential for improving outcomes,” says study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center.
The concentrations of sulforaphane used in the study were higher than what can be achieved by eating broccoli or broccoli sprouts. Prior research suggests the concentrations needed to impact cancer can be absorbed by the body from the broccoli extract, but side effects are not known. While the extract is available in capsule form as a supplement, concentrations are unregulated and will vary.
This work has not been tested in patients, and patients are not encouraged to add sulforaphane supplements to their diet at this time.
Researchers are currently developing a method to extract and preserve sulforaphane and will be developing a clinical trial to test sulforaphane as a prevention and treatment for breast cancer. No clinical trial is currently available.