Hidden Risk

Examining the link between breast density and cancer

There are many variations to women’s breasts, but the important differences are more than meets the eye. One of them — high breast density — is a major risk factor for breast cancer.

Some women’s breasts contain a lot of fatty tissue. Others have more dense glandular tissue that changes in response to hormones associated with menstruation, pregnancy and menopause. Women with dense tissue in more than 75 percent of the breast have a risk of breast cancer that is four- to six-times higher than women with mostly fatty breast tissue.

Breast density is the third-strongest known risk factor for breast cancer, after age and mutations in the BRCA1 or BRCA2 genes, but no one knows why.

Julie Douglas, Ph.D., an associate professor of human genetics, hopes to find out with help from 1,500 Old Order Amish women in Lancaster County, Pennsylvania. She is the principal investigator on a five-year, $3 million NIH-funded study to identify genes that affect breast density. Doing so is the first step to understanding the link between breast density and cancer, which Douglas says could account for about one-third of all cases of the disease.

“One of the advantages of studying the Amish is that they have unique cultural and reproductive behaviors that reduce the effect of non-genetic factors such as delayed childbearing, use of contraceptives and hormone therapy,” Douglas says.

The most common and inexpensive way to measure breast density is with a mammogram. Fatty tissue appears dark on a mammographic image, while dense tissue and tumors show up as white. It’s harder to spot tumors against a white background, which is why radiologists are interested in the amount of density in the image.

Douglas says the study wouldn’t be possible without the expertise of U-M collaborators Heang-Ping Chan, Ph.D., professor of radiology, and Mark Helvie, M.D. (Residency 1986), professor of radiology and director of the breast imaging program. The pair and their colleagues developed a computer-assisted method that classifies each pixel in a mammographic image as black or white, then calculates breast density by finding the ratio between the number of white pixels and total pixels in the image. “It gives us a reproducible quantitative measurement,” Douglas says.

To analyze the complex set of factors related to breast density, Douglas collects massive amounts of data about the Amish women enrolled in the study. A Lancaster radiologist takes screening mammograms for each woman and sends thems to the U-M to be digitized and scored for density. DNA is extracted from blood samples. Blood tests measure individual levels of hormones and other factors. Characteristics like height, weight, body mass index and number of live births are captured and recorded in a database.

Since all the women in the study are descendants of original Lancaster County settlers, Douglas has been able to connect them in one 13-generation pedigree.

“We have hundreds of pairs of sisters, thousands of pairs of first cousins and tens of thousands of more distantly related cousins,” Douglas says. “Having all these pair-wise relationships will allow us to compare genomes of related women with similar breast density scores and identify genes in common.”
—SALLY POBOJEWSKI

Learn more about Douglas and her research

UTI Vaccine Shows Promise

Medical School scientists have taken a major step toward a vaccine to prevent uncomplicated urinary tract infections — a disease that strikes 53 percent of women and 14 percent of men at least once in their lives. Untreated urinary tract infections can lead to permanent kidney damage, and people with repeated UTIs can develop resistance to antibiotics used to treat the condition.

The U-M vaccine works by priming the body’s immune response to specific proteins on the surface of uropathogenic strains of Escherichia coli, the bacterium that causes most uncomplicated UTIs. When U-M scientists tested the experimental vaccine in mice, it generated a strong immune response to these bacterial proteins and prevented mice from being infected with E. coli bacteria in their urinary tracts. If the vaccine works as well on people as it did in mice, it could lead to the first UTI vaccine available in the United States.

Administered through the nose, the vaccine induces an immune response in mucosal tissue lining the urinary tract, which helps the body fight infection where it starts, says Harry L.T. Mobley, Ph.D., the Frederick G. Novy Collegiate Professor and chair of microbiology and immunology, who directed the research.

“The results of our initial animal studies were very encouraging,” says Mobley. “Now, we hope to connect with clinicians and move on to a phase 1 clinical trial in humans.” The U-M has applied for patent protection and is looking for licensing partners to help move the vaccine to market.
—SP

An expanded version of the story
Patient information on UTIs

Stimulus Funding Reaches Medical School

Medical School researchers are a big reason the University of Michigan has received $47.5 million in federal research funding to date from the federal economic stimulus package known as the American Recovery and Reinvestment Act.

“Despite the recent slowdown in federal funding for biomedical research, our faculty has succeeded in obtaining government funding for many important new projects,” says Steve Kunkel, Ph.D., senior associate dean for research. “These new stimulus grants will help us conduct research to solve medical challenges, speed innovations from the lab to the bedside, train tomorrow’s researchers and provide upgraded laboratory facilities and equipment.”

Some research awards will fund Medical School scientists studying potential treatments for epilepsy, cardiac arrhythmias and cancer. Other awards are supporting efforts to develop a vaccine to protect children from ear infections and an imaging-based system to determine if cancer treatments are working. Kunkel expects additional stimulus grants to be awarded in future months.
—SP

Mice Stay Younger, Longer

In research supported by the National Institute on Aging, Richard Miller, M.D., Ph.D., studies drugs with the potential to delay disease and slow aging in mice. Treatments that slow down the aging process in mice might do the same for people someday.

Although he’s tested several promising candidates, Miller says a drug called rapamycin is the new front-runner in anti-aging research. In independent studies conducted at three NIA-funded research institutions, rapamycin extended the lifespan of middle-aged mice from 9 percent to 14 percent compared to animals that didn’t receive the drug.

“While other results have been promising, the rapamycin effect is bigger and worked even when started in late middle-age,” says Miller, a professor of pathology and associate director of research at the U-M Geriatrics Center.
—SP

An expanded version of the story

Cell Replacement for Parathyroid Takes Major Step

Using human embryonic stem cells, researchers at the U-M Medical School have created live cultures of parathyroid-like cells that secreted an essential calcium-regulating hormone called PTH. The research is an important step toward a new cell transplant therapy to help patients with damaged or diseased parathyroid glands.

“We used human embryonic stem cells as a model to work out the recipe to make parathyroid cells,” says Gerard M. Doherty, M.D., the Norman W. Thompson Professor of Endocrine Surgery. Federally approved embryonic stem cell lines used in the study were supplied by the Michigan Center for Human Embryonic Stem Cell Research.

Humans have four rice grain-sized parathyroid glands located in the neck next to the thyroid gland. If they become diseased or are damaged during surgery, they stop secreting PTH. Without this calcium-regulating hormone, patients develop osteomalacia — a form of bone loss similar to rickets.

Doherty’s ultimate goal is to use cells from a patient’s thymus gland to regenerate functioning parathyroid cells. Using the patient’s own cells would eliminate the need for immunosuppressive drugs to prevent the immune system from rejecting the cell transplants. If all goes well, Doherty says an effective cell replacement therapy could be available within five to 10 years.
—SP

An expanded version of the story
Patient information on parathyroid glands

Nano for Burns?

Medical School scientists have shown that a nanoemulsion lotion, developed at the U-M and licensed to NanoBio Corporation, sharply curbed bacterial growth and reduced inflammation in animals with second-degree burns. According to Mark Hemmila (M.D. 1994), associate professor of surgery, the nanoemulsion could eventually replace existing topical antimicrobial agents, which have a limited ability to penetrate burned skin and kill sub-surface bacteria, and don’t have a strong effect on inflammation. Before testing in people, additional research is needed to examine the nanoemulsion’s effects on the overall healing process.
—SP

An expanded version of the story

Targeting IPF

Idiopathic pulmonary fibrosis, or IPF, causes progressive lung scarring and thickening that make it difficult, and eventually impossible, to breathe. There is no treatment and the average survival time after diagnosis is less than three years. But now Medical School researchers have developed a new experimental treatment for IPF that stopped the progression of fibrosis in mice and preserved their lung function. Treatment inhibits the activity of an enzyme called NOX4, which U-M scientists discovered is key to the formation of fibrotic scar tissue in the lungs and other organs. The researchers plan to develop the treatment for future testing in human patients.
—SP

An expanded version of the story

Understanding Immune Response

What keeps aggressive immune system T cells from attacking the body’s own cells? Part of the answer, according to Ruma Banerjee, Ph.D., the Vincent Massey Collegiate Professor of Biological Chemistry, is in the chemical environment between the cells. A new study from Banerjee’s research team found that regulatory T cells can change this environment in ways that either cool down or ramp up the immune response. Understanding how this mechanism works could lead to new treatments for autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and lupus.
—SP

An expanded version of the story