Breast cancer is the second leading cause of cancer death in women, and one out of every eight American women will be diagnosed with breast cancer during her lifetime. During Breast Cancer Awareness Month every October, the world is awash with pink as we celebrate the survivors and mourn the 40,290 women who die from the disease every year, according to the American Cancer Society. Behind those statistics are the real people and the real families who are desperate for a cure. There are still so many unknowns about the disease, including how to prevent it and how best to treat it; and researchers at the Texas A&M Health Science Center are actively working to answer these questions.

“I knew from the beginning that I wanted to study cancer, and breast cancer is such an important and prevalent disease,” said Robin Fuchs-Young, Ph.D., a professor in the Department of Molecular and Cellular Medicine at the Texas A&M College of Medicine and the Texas A&M Institute for Biosciences and Technology. “I was always surprised about how little we knew about why it happens.”

And the work in Fuchs-Young’s lab focuses on just that, why some women get breast cancer and others don’t: an area of research called differential susceptibility. They study a number of factors—from genetics and ethnic background to diet and number of pregnancies—that are thought to influence breast cancer risk.

Fuchs-Young is also interested in why some women get types of cancer with good prognoses that are relatively easy to treat and why others get the types of breast cancer that are much more aggressive. “An underlying theme of our research is the discovery of molecular, cellular and physiological determinants of disparities in breast cancer incidence and outcome,” she said.

To do this, the researchers study the basic mechanisms of the development of breast cancer, including how molecules act and function to enhance tumors. They are also looking for ways to predict, on the cellular and molecular level, what the optimum treatment is and what the outcome is likely to be.

Factors that go into a prognosis include a woman’s age when diagnosed, her menopausal status, size of the tumor and whether the cancer has metastasized. “Those classical kinds of parameters are used still, because they’re very important,” Fuchs-Young said. “We know a lot about what they tell us.” Still, cellular and molecular indicators are now used to be even more specific. A pathologist can determine whether the breast cancer cells are positive or negative for estrogen receptors, progesterone receptors and HER2. Between 15 and 20 percent of breast cancers are found to be triple-negative, meaning they are negative for all three, and these are among the most difficult kind to treat because they do not respond to drugs that inhibit hormones or HER2 receptors.

It also seems tumors that are different on the molecular and cellular level may have different risk factors. For example, although becoming pregnant at a young age lowers a woman’s risk of breast cancer, it does not seem to give the same level of protection against cancers that occur early and are estrogen-receptor-negative.

Proteins that promote breast cancer

Fuchs-Young and her team have one of the only animal models of overexpression of a small peptide hormone called the insulin-like growth factor 1 (IGF-1), which is thought to play a critical role in breast cancer development.

It does so via an unusual mechanism, though. “We have found out that it acts differently than people thought it did,” Fuchs-Young said. “Everyone had thought it was a classical tumor promoter, but we found that it probably also acts by expanding the tissue stem cell population during early mammary gland development.” In other words, shortly before and during puberty, high levels of this small protein leads to more stem cells—which can affect breast cancer risk.

“These results indicate that elevated IGF-1 levels during early development contribute to a lifetime risk of breast cancer,” Fuchs-Young said. “These findings are critical for elucidating the factors that contribute to breast cancer susceptibility” because young African-American girls tend to have significantly higher circulating levels of IGF-1 than Caucasian girls of the same age. These higher levels of IGF-1 may help account for increased incidence of early-onset and aggressive breast cancer subtypes in women of African descent.

The researchers are also looking at ethnic differences in the gene that codes for tumor protein p53. Some research has indicated that p53 might be correlated with early-onset, estrogen-receptor-negative breast cancer, and Fuchs-Young and her team are looking at samples of human breast cancer tissue to see if this is indeed the case.

“Finding that it is correlated would be something that could be readily translated into a clinical setting,” Fuchs-Young said. “Although it is unlikely that this variant alone is the whole story, we think that looking at p53 in this context may provide additional insight into risk. It might also help physicians make a more accurate prognosis for women who have already been diagnosed with breast cancer.”

Diet and Exercise

Fuchs-Young and her team have also been studying how the mother’s diet during gestation impacts the offspring’s likelihood of developing breast cancer in the future. Although results are preliminary, they suggest that if the developing fetus is exposed to a high-fat, high-sugar diet, and then later in life maintains a healthy diet with mild restriction (for humans this would be the equivalent of practicing portion control), their risk of developing mammary cancer decreases.

At slightly higher risk were animals who were given a high-fat, high-sugar diet for their entire lives and those that were given a calorie-restricted diet for their entire lives, although, oddly, these two groups had similar risk to each other.

“What our work is showing is that what matters is the interaction between what you’re exposed to early, and what you’re exposed to later,” Fuchs-Young said.

At greatest risk were cases where the pregnant and lactating mother is on a restricted diet and then her offspring was fed a high-fat, high-sugar diet. Some epidemiological studies in humans have hinted that this sort of extreme situation, where people were terribly deprived, such as during a war, and later in life have had access to ample calories, can lead to major health problems, but it hasn’t specifically been studied in regards to breast cancer.

“There are many caveats before we start saying that this definitely applies to people,” Fuchs-Young cautioned. “But it’s interesting, and we’re going to try to understand the mechanisms involved in these processes.”

These studies are still ongoing, and the researchers are also trying to determine how exercise fits into the picture.

“We’re still waiting for the data about the effect of voluntary physical activity on susceptibility to breast cancer,” Fuchs-Young said. “Understanding the disease better puts us in a position to not only treat it more effectively, but also to potentially identify some strategies for prevention.”

— Christina Sumners

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