Breast cancer linked to obesity gene, new research suggests

ScienceDaily (May 23, 2011) — New research aimed to better identify the genetic factors that lead to breast cancer has uncovered a link between the fat mass and obesity associated gene (FTO) and a higher incidence of breast cancer. According to the study conducted at Northwestern Memorial Hospital, people who possess a variant of the FTO gene have up to a 30 percent greater chance of developing breast cancer. Research to identify why the link exists is ongoing, but experts say the finding takes us one step closer to personalized medicine based on genetic risk which would allow for better monitoring and prevention of illness, as well as targeted treatment.

See Also:Health & MedicineBreast CancerPersonalized MedicineCancerDiseases and ConditionsColon CancerOvarian CancerReferenceBRCA1BRCA2Tumor suppressor geneBreast reconstruction

"This is a fascinating early finding, which fits with the known connections between obesity and breast cancer," said Virginia Kaklamani, MD, oncologist at Northwestern Memorial, co-director of the Cancer Genetics Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and lead author of the study.

Each individual carries the FTO gene, but only 18 percent have this variant of the gene. Kaklamani, who specializes in cancer genetics, says testing for the FTO variant is not available currently, but it may be available in the future, similar to how genetic testing for the BRCA gene mutation exists today.

"Ten years ago we didn't know about the BRCA gene mutation which has been linked to breast and ovarian cancer. Today, we offer genetic testing and a specialized clinic for those at risk in order to minimize their risk and detect any indication of cancer early," said Kaklamani, who is also an associate professor of medicine at Northwestern University Feinberg School of Medicine. "This knowledge helps us better identify who is at an increased risk so one day, we can counter that risk through preventative measures and advanced screening."

The research, published in BMC Medical Genetics is part of an ongoing group of studies to further knowledge of genetic risk factors for breast cancer.

Email or share this story:

Acetaminophen linked to lower prostate cancer risk in new study

ScienceDaily (May 24, 2011) — A new study from American Cancer Society researchers finds use of 30 tablets a month or more of acetaminophen for five or more years was associated with an estimated 38% lower risk of prostate cancer. The study appears in Cancer Epidemiology, Biomarkers and Prevention and is one of only two studies of prostate cancer to date that have examined the association with acetaminophen use that was both long-term and regular.

See Also:Health & MedicineProstate CancerMen's HealthUrologyProstate HealthBreast CancerCancerReferenceHealth benefits of teaUrologyLavender oilMetastasis

Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), particularly long-term use, has been associated with modestly reduced risk of prostate cancer in some previous epidemiologic studies. Acetaminophen, a commonly used pain-reliever, is not traditionally considered an NSAID but can have anti-inflammatory effects.

For the current study, researchers led by Eric Jacobs, Ph.D., American Cancer Society epidemiologist, examined the association between acetaminophen use and prostate cancer incidence among 78,485 men in the Cancer Prevention Study II Nutrition Cohort. Information on acetaminophen use was obtained from a questionnaire completed at study enrollment in 1992 and updated using follow-up questionnaires in 1997 and every two years thereafter.

During follow-up from 1992 through 2007, there were 8,092 incident prostate cancer cases identified. Current regular use of acetaminophen (> 30 pills per month) for 5 years or more was associated with lower risk of overall prostate cancer (RR

Hormone precursor inhibits brain inflammation: Molecule moderates condition linked to neurodegenerative diseases

ScienceDaily (May 15, 2011) — Researchers at the University of California, San Diego School of Medicine have discovered a steroid hormone that inhibits inflammation in the brain. The findings, to be published in the May 13 issue of the journal Cell, have implications for understanding the exaggerated inflammatory responses that are characteristic features of numerous neurodegenerative diseases.

See Also:Health & MedicineImmune SystemCrohn's DiseaseHormone DisordersMind & BrainDisorders and SyndromesAlzheimer'sParkinson'sReferenceMyelinInflammationNatural killer cellAstrocyte

The discovery that the steroid hormone ADIOL, (5-androsten-3Β-17Β-diol), a precursor of androgens and estrogens, modulates inflammation induced by microglia cells could eventually lead to new treatments for patients with neurodegenerative conditions in which inflammation plays a pathogenic role. In addition, levels of ADIOL in blood or other body fluids might be useful for predicting risk or responses to drugs that mimic its actions.

The senior author of the paper is Christopher Glass, MD, PhD, professor of the department of cellular and molecular medicine and the department of medicine. Lead author is Kaoru Saijo, MD, PhD, and an associate project scientist in the Glass lab.

Though neurons get the headlines, they thrive only with the support of other cell types, among them microglia and astrocyte cells. Microglial cells help the central nervous system respond to infection and injury. Under normal conditions, they exist in a resting state, quietly but constantly surveying their surrounding environment for tell-tale indications of microbial invasion or tissue damage. Once detected, microglia initiate an inflammatory response, kick-starting immune system and tissue repair processes. Astrocytes amplify the immune reaction launched by microglia.

The microglia-astrocyte activation is vital to an effective immune response and damage repair, but if the resulting inflammation induced by these cells is not controlled or goes on too long, it can result in damage and death to neurons. Inflammation run amok is linked to many neurodegenerative diseases, such as Parkinson's disease, HIV-associated dementia, Alzheimer's disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), and some inflammatory diseases like multiple sclerosis (MS).

The new findings suggest that in healthy brains, microglia inflammation is modulated by the production of the steroid hormone ADIOL, which instructs support cells to calm down and return to their quiescent state. ADIOL works by binding to a transcription factor called estrogen receptor Β, which gets its name because of its similarity to estrogen receptor Β and its ability to bind to the female sex hormone estrogen. Unexpectedly, while ADIOL binding causes estrogen receptor α to execute an anti-inflammatory set of instructions to microglia and astrocytes, estrogen binding does not. Because of this, estrogens can actually antagonize the anti-inflammatory actions of ADIOL.

Glass and Saijo made their discovery based upon initial studies with John Katzenellenbogen, PhD, at the University of Illinois, Urbana-Champaign. Kaztenellenbogen's laboratory developed a number of synthetic small molecules that could bind very tightly and specifically to estrogen receptor .

Saijo at UC San Diego tested each of these compounds and found that some were potent inhibitors of inflammatory responses of microglia and astrocytes, while others were not. When one of these compounds was tested in vivo, it was found to strongly inhibit inflammation in the brain and to induce remission in a mouse model of multiple sclerosis.

Although estrogen itself can be neuroprotective, its lack of ability to induce the anti-inflammatory activity of estrogen receptor  led to a search for endogenous or internal molecules that might have similar activities to the synthetic compounds. Saijo worked with Andrew Li, MD, assistant adjunct professor of medicine at UC San Diego, to ultimately identify ADIOL as the endogenous regulator of estrogen receptor  activity. Notably, Saijo and Li found that the amount of ADIOL that could be produced by microglia was regulated by signals that control the magnitude and duration of inflammatory responses

"We think it possible that mutations in the genes encoding the key enzymes for the generation of ADIOL, or their inappropriate down-regulation, could contribute to pathological forms of inflammation," Glass said.

These findings raise the possibility that women are more susceptible to certain inflammatory diseases, such as MS, because their higher levels of estrogens potentially antagonize the anti-inflammatory actions of ADIOL in the brain. A similar argument might also help explain some of the adverse effects of estrogen administration on the brain in post-menopausal women.

Glass noted, however, that much research remains to be done. The precise relationship between brain inflammation and neurodegenerative disease, for example, is not fully understood. Similarly, it's not known whether people naturally produce different amounts of ADIOL. And researchers have only identified the ADIOL-estrogen connection in an MS mouse model. Glass said he and colleagues will next look at animal models for Alzheimer's, Parkinson's and HIV-dementia.

Co-authors of the study include Jana G. Collier, UCSD Department of Cellular and Molecular Medicine.

Funding for this study was provided by the National Institutes of Health.

Email or share this story:

Obesity linked to higher risk of prostate cancer progression

ScienceDaily (May 16, 2011) — Even when treated with hormone therapy to suppress tumor growth, obese men face an elevated risk of their prostate cancer worsening, researchers at Duke University Medical Center have found.

See Also:Health & MedicineMen's HealthProstate CancerUrologyProstate HealthObesityDiseases and ConditionsReferenceGeneral fitness trainingUrologyMetastasisTestosterone

The research, reported at the American Urological Association annual meeting on May 15, 2011, advances the link between obesity and prostate cancer, which has generated research interest in recent years as the incidence of both conditions remains high and often overlaps.

"Over the past decades, there has been increasing prevalence of obesity in the U.S. and Europe, and a high rate of prostate cancer that is the second-most lethal cancer for men," said Christopher J. Keto, M.D., a urologic fellow at Duke University Medical Center and lead author of the study.

An estimated one in six U.S. men will be diagnosed with prostate cancer during his lifetime, according to the American Cancer Society; additionally, one in three U.S. men are obese.

To examine the role obesity may play in prostate cancer, Keto and colleagues at Duke identified 287 men whose diseased prostates had been removed at five U.S. Department of Veteran Affairs hospitals from 1988-2009.

Because their cancers had reappeared, the men had also been given androgen deprivation therapy (ADT). The chemical inhibits production of the male hormone testosterone, which fuels prostate tumors.

Men in the study group who were overweight or obese had a three-fold increased risk of cancer progression compared to normal-weight men, despite receiving the same treatment.

Additionally, overweight men had more than a three-fold increased risk of their cancer spreading to the bone compared to normal-weight men, while obese men had a five-fold increase in the risk of metastases.

Keto said additional studies are needed to determine why heavy men fare worse than normal-weight men, even when treated similarly. One area of scrutiny may be the dosage of ADT.

"We think perhaps obese men may require additional ADT," Keto said. "The dose is the same regardless of weight, while most drugs are dosed according to weight."

Stephen J. Freedland, M.D., associate professor of urology in the Duke Prostate Cancer Center and senior author of the study, said the findings build upon the Duke group's broader research efforts into the connection between obesity and prostate cancer.

"By being thematic in our research we can really get to the bottom of something," Freedland said. "The study supports a growing body of literature showing that obese men with prostate cancer do worse. Our next step is to figure out why."

Freedland said knowing that heavy men are at higher risk for bad outcomes could lead to better interventions. He said the Duke group has launched a new trial to test the effects of diet and exercise on overweight and obese men whose prostate cancer treatment includes hormone therapy.

"If obesity is bad for prostate cancer, we may have to be more aggressive in our treatment," he said. "Ultimately, we aim to learn why, which in turn can lead us to better treatments for these men."

In addition to Keto and Freedland, study authors included William J. Aronson, M.D.; Martha K. Terris, M.D.; Joseph C. Presti, M.D.; Christopher J. Kane, M.D.; and Christopher L. Amling, M.D.

The study was funded by the Department of Defense, U.S. Department of Veterans Affairs, the National Institutes of Health, and the AUA Foundation/Astellas Rising Star Award.

Email or share this story:

Cell rigidity linked to activity in proteins associated with cancer

ScienceDaily (May 16, 2011) — An unusual collaboration between cell and developmental biologists and physicists at UNC-Chapel Hill is providing insights into the relationship between the physical properties of cells and the signals that influence cell behavior.

See Also:Health & MedicineLung CancerStem CellsBrain TumorCancerOvarian CancerLymphomaReferenceHeat shock proteinMetastasisTumor suppressor geneNatural killer cell

In a paper published online May 15 in the journal Nature Cell Biology, a team led by Keith Burridge, PhD, Kenan distinguished professor of cell and developmental biology and a member of UNC Lineberger Comprehensive Cancer Center, and Richard Superfine, PhD, Taylor-Williams distinguished professor of physics and astronomy, demonstrates that exerting mechanical force on cells activates Rho GEF proteins through distinct signaling pathways. The Rho GEFs activate Rho proteins that are part of the RAS superfamily -- a class of proteins associated with cancer activity.

The cross-disciplinary team applied magnetic particles to cells and then used magnets to exert force on the cells -- creating extracellular tension.

"This experiment was only possible because we were able to bring together a team of physicists and cell biologists," said Burridge.

"It's very exciting because we have identified the entire pathway between the tension exerted on the cell to proteins that, in turn, activate other proteins that we know tend to be hyperactive in cancer," he added.

Scientists have long believed that the mechanical environment of cells affects their growth and properties. For example, solid tumor cells tend to have an altered stiffness. Other researchers have shown that the stiffer the cell matrix, the worse the prognosis. There is evidence that rigid tumors shed more cells, which escape the original tumor site and may lead to a greater chance of cancer spreading through metastasis.

"There has been a hypothesis that cell stiffness and tension create a vicious cycle leading to enhanced growth, more cell density, more tension, and larger tumors," said Burridge. "Innovation funding from the University Cancer Research Fund allowed us to identify the pathway and provided data that resulted in a grant renewal worth approximately $1.3 million over the next four years."

In addition to Burridge and Superfine, the research team included postdoctoral fellow Christophe Guilluy, PhD, and assistant professor Rafael Garcia-Mata, PhD, from the Department of Cell and Developmental Biology and graduate student Vinay Swaminathan, PhD, and assistant professor E. Timothy O'Brien, PhD, from the Department of Physics and Astronomy.

In addition to the UCRF innovation grant, this research was supported by the National Institutes of Health and a Marie Curie Outgoing International Fellowship from the European Union Seventh Framework Programme.

Email or share this story:

Obstructive sleep apnea linked to cancer growth in mice

ScienceDaily (May 17, 2011) — A new study links the intermittent interruption of breathing that occurs in patients with obstructive sleep apnea (OSA) to enhanced proliferation of melanoma cancer cells and increased tumor growth in mice, according to researchers in Spain. The study also found tumor cells of OSA mouse models tended to contain more dead cells, indicating a more aggressive type of cancer.

See Also:Health & MedicineBrain TumorSleep Disorder ResearchCancerOvarian CancerLung CancerColon CancerReferenceHeat shock proteinMetastasisObstructive sleep apneaGlioma

The results of the study will be presented at the ATS 2011 International Conference in Denver.

"To our knowledge, this study is the first one providing experimental evidence that a high-rate intermittent lack of oxygen, or hypoxia, mimicking the one experienced by OSA patients enhances tumor growth," said Ramon Farre, PhD, professor of physiology at the University of Barcelona School of Medicine Biophysics and Bioengineering Lab.

Recurrent hypoxia is one of the hallmarks of OSA, which may affect around 5 percent of Americans. OSA has been associated with an increased risk of cardiovascular disease, including high blood pressure, as well as daytime sleepiness and a lower quality of life.

"Although earlier studies in animals have shown that lack of oxygen, or hypoxia, plays an important role in regulating the various stages of tumor formation and progression, the results obtained from human studies including large groups of OSA patients are not easy to interpret because there are other contributing conditions, most notably obesity," Dr. Farre added. "This well-controlled mouse model study allowed us to ensure that the only variable under study was intermittent hypoxia."

In this study, mice injected with melanoma tumor cells were divided among two groups. In the first group, mice were exposed to intermittent hypoxia, where oxygen was restricted for 20-second periods at a rate of 60 periods per hour for six hours per day, and normal oxygen levels for the remainder of the day. In the second group, mice received normal levels of oxygen (normoxia). Tumor volume was measured throughout the study and at the end of the study period. At the end of the 14-day study period, tumors from all mice were removed and weighed and tumor necrosis (indicated by the numbers of dead cells present) was measured to determine the aggressiveness of the tumors.

The authors found that while tumor volume progressively increased with time in both the intermittent hypoxia and control groups, the increase was higher in the mice subjected to intermittent hypoxia. Tumor weight and necrosis in the intermittent hypoxia group were almost two times that of the tumors in the control group.

"With the limitations of any animal model study, these results suggest that the intermittent hypoxia characterizing obstructive sleep apnea could enhance the growth of tumors," Dr. Farre said, adding that although the results were not entirely unexpected based on earlier studies connecting hypoxia with tumor growth, a link between breathing abnormalities specific to OSA and tumor progression had not previously been demonstrated.

"It was well known that continuous hypoxia promotes the growth of cancer cells and tumors," he said. "However, there were no data concerning the effects of the fast rate changes of oxygenation in sleep apnea on cancer."

Dr. Farre said the results of this study could have future clinical implications if the results are confirmed in large-scale human studies. "There are still several questions that need to be answered, both at the basic science and clinical levels," he said.

Future studies would need to evaluate whether intermittent hypoxia also triggers the initial formation of tumors and whether it promotes metastasis, or spread of tumors from one organ to another. Because this study focused on melanoma, Dr. Farre said additional studies should also explore whether intermittent hypoxia affects other types of cancer.

Extended population studies should also determine if there is a relationship between the incidence of cancer and the severity of OSA, as well as addressing the issue of obesity, which has been linked with OSA.

"Intermittent hypoxia is not the sole cancer-promoting challenge experienced by OSA patients," Dr. Farre said. "Obesity is also known to enhance cancer morbidity and mortality, and it is not clear to what extent intermittent hypoxia and obesity could interact to increase cancer growth in OSA patients.

Clarifying these questions certainly will require additional studies," he said. "If the current results in an animal model are confirmed by further clinical research, the public health impact of obstructive sleep apnea would be greater than currently known."

Email or share this story: