Clues to Pregnancy-Associated Breast Cancer Found

Expression of inflammatory-related genes in breast tissue of women who have previously given birth may explain the aggressiveness and frequency of pregnancy-associated breast cancer, according to new research at the University of Illinois at Chicago.

Pregnancy at a relatively young age reduces the risk of breast cancer over the long term, but epidemiological studies have found that women are at an increased risk for breast cancer during pregnancy and for up to 10 years after giving birth, said Debra Tonetti, associate professor of pharmacology and lead researcher on the study. These pregnancy-associated breast cancers also carry an unusually high risk of spreading to nearby organs and for lethality as compared to breast cancers in women who have never been pregnant, she said.

Tonetti and her research team examined the level of expression of 64 genes in tissue from benign breast biopsies and breast-reduction surgeries at the University of Illinois Medical Center at Chicago. The women, who were between the ages of 18 and 45, were divided into three categories: those who had never been pregnant, those who had been pregnant within the past two years, and those who had been pregnant five to 10 years previously.

The set of examined genes included genes known to be related to immunity and inflammation, extracellular matrix remodeling, angiogenesis (the growth of new blood vessels vital to wound healing) or hormone signaling.

Twenty-two percent of the examined genes showed significant difference in expression in the breast tissue of women who had never given birth compared with those who had. Inflammation-related genes, as a class, were more active in women who had borne a child. Involution -- the process by which the breast returns to normal following lactation -- could be a cause of the inflammation, she said.

"Our results showed an increase in immune/inflammatory activity in the post-pregnant breast," Tonetti said. "Interestingly, this response was not limited to the recently pregnant group, but also characterized more distant pregnancies as well."

A surprising finding was evidence of a protective effect of pregnancy as well, since the expression of many hormone and growth factor signaling genes suggests protection. These findings indicate that a balance between high risk inflammatory and protective hormone signaling gene expression may ultimately determine a woman's individual breast cancer risk, she said.

The researchers were not only interested in determining whether pregnancy and involution are associated with gene expression changes in the normal breast, but whether such changes stay for a short period of time or are permanent, Tonetti said.

The study is among the first to use samples from normal breast tissue to determine whether there is a time-dependent effect on breast cancer risk, she said.

The results will help understand the mechanisms behind pregnancy-associated breast cancer and will indicate potentially effective prevention strategies for women at high risk, such as use of anti-inflammatory agents. In addition, more effective therapeutic approaches may be developed based on the specific molecular pathways involved, Tonetti said.

The findings are published in the March issue of the journal Cancer Prevention Research. The study was funded through a grant from Avon Products Foundation.

Other authors, all from UIC, include Szilard Asztalos and Megan Hayes of the department of biopharmaceutical sciences; Peter Gann, Larisa Nonn and Elizabeth Wiley of the department of pathology; Craig Beam of the department of epidemiology and biostatistics; and Yang Dai of the department of bioengineering.

Cocaine-Related Deaths Rise in Warm Weather, Study Finds

In a study published online in the journal Addiction, researchers in the United States have discovered that accidental overdose deaths involving cocaine rise when the average weekly ambient temperature passes 24 degrees Celsius (75 degrees Fahrenheit).

Using mortality data from New York City's Office of the Chief Medical Examiner for 1990 through 2006, and temperature data from the National Oceanic and Atmospheric Association, researchers found that accidental overdose deaths that were wholly or partly attributable to cocaine use rose significantly as the weekly ambient temperature passed 24 degrees Celsius. The number of cocaine-related overdose deaths continued to rise as temperatures continued to climb.

Cocaine-related overdose deaths increase as the ambient temperature rises because cocaine increases the core body temperature, impairs the cardiovascular system's ability to cool the body, and decreases the sense of heat-related discomfort that ordinarily motivates people to avoid becoming overheated. Cocaine users who become overheated (hyperthermic) can overdose on lower amounts of cocaine because their bodies are under more stress.

The study's findings correct previous research that associated an increase in cocaine-related mortality with much higher temperatures (31.1 degrees Celsius, or 87.9 degrees Fahrenheit). Because cocaine-related overdose fatalities begin to rise at lower ambient temperatures than was previously thought, it is now apparent that cocaine users are at risk for longer periods of each year. Between 1990 and 2006, the average weekly temperature in New York City rose above 24 degrees Celsius for about seven weeks per year.

The study showed no difference in the number of drug overdoses in New York City among those weeks where the average temperature was between -10 and 24 degrees Celsius. Above 24 degrees Celsius, however, there were 0.25 more drug overdoses per 1,000,000 residents per week for every two degrees increase in weekly average temperature. Given that over 8.2 million people live in New York City, the study's findings predict that at least two more people per week will die of a drug overdose in the city for each two degree rise in temperature above 24 degrees Celsius, compared to weeks with average temperatures of 24 degrees and below.

The authors of this study point out the need for public health interventions in warm weather, such as delivering health-related warnings to high-risk groups. Prevention efforts could also include making air conditioning available in locations where cocaine use is common such as urban areas with a known high prevalence of cocaine use, and within those urban areas, particular neighbourhoods with elevated numbers of cocaine-related deaths or arrests. As lead author Dr. Amy Bohnert explains, "Cocaine users are at a high risk for a number of negative health outcomes and need public health attention, particularly when the weather is warm."

Infectious Virus Hidden in Chromosomes Can Be Passed from Parents to Children

Human herpesvirus 6 (HHV-6) infects nearly 100 percent of humans in early childhood, and the infection then lasts for the rest of a person's life. Now, a team led by Peter Medveczky, MD, a professor in the Department of Molecular Medicine at the University of South Florida (USF), has discovered that in some individuals, HHV-6 causes such a permanent infection by inserting or "integrating" its DNA into human chromosomes. From this harbor, the viral DNA cannot be eliminated by the immune system.

The paper describing this research was published online March 8 in Proceedings of the National Academy of Sciences.

The USF team also confirmed preliminary results by other investigators that, a long time ago, the virus inserted its DNA into the DNA of human sperm and egg cells. As a result, some people (about 1 percent of people in the U.S.) are born with the virus's DNA in every cell in their body. Indeed, HHV-6 is the first functional virus of any type reported to be passed through the human germ line.

The team presented clear evidence that the virus can insert its DNA specifically into telomeres -- structures at the ends of each chromosome that play key roles in both aging and cancer.

Finally, the team showed that the chromosomally integrated HHV-6 (CIHHV-6) genomes can be reactivated to an infectious form.

The findings are a surprise, since other human herpesviruses cause permanent infection by a different mechanism. The round up their DNA into a little circle that resides inside the nucleus of the cell: they do not insert their DNA into the chromosomes.

There are many unanswered questions that the USF team hopes to sort out. "We would like to know whether the location of the integration has an impact on pathology," Dr. Medveczky said. "We'd also like to know more about which drugs can provoke reactivation in patients that carry this virus in every cell... It would be important for these patients to avoid drugs that may reactivate the virus."

"This is an exciting and provocative series of observations. The questions raised by this work will keep herpes virologists busy for years," predicted HHV-6 expert Phil Pellett, PhD of Wayne State University.

HHV-6 was discovered in 1986 in the laboratory of Dr. Robert C. Gallo at the National Cancer Institute after Gallo asked his co-workers to look for a herpesvirus in AIDS lymphoma cases that might be triggering cancer. "In my mind these findings also should stimulate further studies on a possible role of HHV-6 in some cancers as suggested by others who have found a possible link to some lymphomas," Dr. Gallo commented. "However, clearly more work will be needed to advance any conclusion in this regard."

HHV-6 causes roseola, a generally benign rash and fever in infants. The virus can reactivate in individuals with suppressed immune systems, sometimes causing serious consequences such as encephalitis, hepatitis, myocarditis, and pneumonia.

Recent research has suggested that HHV-6 may also be associated with diseases in people with apparently healthy immune systems: encephalitis, mesial temporal lobe epilepsy, multiple sclerosis, myocarditis, and idiopathic cardiomyopathy. While there is no proof that the virus plays a causal role in these diseases, the virus has been found more often in the diseased tissue than in healthy tissue.

Previous studies had used a visual technique called fluorescence in situ hybridization (FISH), which showed that the viral DNA was present at the same location (near the telomeres) of the same chromosome in both parent and child. This strongly suggested but did not prove that the virus was inherited through the germ line in these children. By determining the DNA sequence of the ends of the chromosome, the Medveczky team clearly demonstrated that the HHV-6 genome was integrated into telomere DNA. The team also showed that HHV-6 DNA, unlike other human herpesviruses, does not curl into a circle inside the nucleus.

The great majority of people, however, do not inherit HHV-6 DNA from their parents and do not have it in every cell of their body. Yet nearly everyone becomes permanently infected with the virus. So Medveczky and colleagues wondered if the virus might take up permanent residence in the body by integrating its DNA into the chromosomes of just some cells.

To examine this possibility, the investigators took cells that had never been exposed to HHV-6 and infected them with HHV-6 that had been engineered to make infected cells glow bright green. Sure enough, once the infection died down, the green cells contained HHV-6 DNA integrated into the ends of the chromosomes. When the investigators stimulated the cells with chemicals known to activate other herpesviruses, cells with integrated viral DNA began producing infectious virus. It will be important to learn whether a similar process occurs during the form of HHV-6 infection that occurs in most individuals.

For the approximately 1 percent of the population born with viral DNA in every cell in their body, several questions arise. Are such people more prone to diseases because they have a greater risk of viral reactivation? If so, which diseases? If a person is born with viral proteins present from birth, would that person's immune system be "fooled" into thinking that the virus was not foreign and need not be attacked? If so, is that a bad thing or a good thing for a person's health? Finally, the virus inserts itself into the telomeres and could theoretically disrupt the function of the telomeres. Since the telomeres are important in cellular aging and in cancer, could the insertion of viral DNA in the telomeres have any effect on a cell's tendency to age or to turn cancerous?

While unique among known human herpesviruses, the capacity of HHV-6 to integrate into human chromosomes is not unique in nature. A herpesvirus that infects chickens, called Marek's disease virus, appears to behave the same way. Interestingly, although the viruses are not otherwise closely related, the DNA sequence used by Marek's disease virus to integrate into chicken chromosomes is remarkably similar to the DNA sequence used for chromosomal integration by HHV-6.

Doctoral student Jesse Arbuckle and research associate Maria Medveczky, both of the USF Department of Molecular Medicine, were lead authors of the study. Other contributing authors were from Bioworld Consulting Laboratories, the HHV-6 Foundation, University of Minnesota, University of Brussels, Stanford University School of Medicine and Harvard Medical School.

The USF study was funded by the HHV-6 Foundation, a non-profit organization that supports virology research, as well as by a grant from the National Institutes of Health.