Study aims to uncover role of tumor-suppressing WWOX gene in triple-negative breast cancer

Why? is one of my favorite questions,” said City of Hope professor Victoria L. Seewaldt, M.D. “I started out as a breast cancer advocate before I became a physician and a researcher, and why is the reason I became an advocate. I don’t like to see something broken without a way to fix it.”

Seewaldt, Ruth Ziegler Professor and Chair, Department of Population Sciences at City of Hope, has been working with Rami I. Aqeilan, Ph.D., Senior Lecturer at the Lautenberg Center for Immunology and Cancer Research at Hebrew University-Hadassah Medical School in Jerusalem, on a study designed to better predict who is at high risk for triple-negative breast cancer (TNBC) because of gene damage or environmental influence. She brings years of experience in breast cancer education, detection, and prevention, as well as expertise in translational research and biomarker signaling, to the partnership, while Aqeilan brings his knowledge of tumor suppressor signaling. Their collaboration is the result of a grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, which was established in 2016 by a gift from the Harvey L. Miller Family Foundation to support the exchange of ideas, strategies, and therapies between City of Hope and Israeli investigators backed by the Israel Cancer Research Fund (ICRF).

“I see women who are at increased risk of breast cancer, and one of the first questions a woman commonly asks when she gets a breast cancer is, ‘Why?’” said Seewaldt, who joined City of Hope in 2015. “This study allows us to get a better fix on how the environment may be tying into breast cancer and ways to try to make things better.”

Triple-negative breast cancers are very aggressive, and patients suffering from them have lower rates of survival than those with other breast cancers. It’s well established that an inherited germline mutation in the BRCA1 gene signals a higher risk of developing breast cancer — as high as 50 percent among Ashkenazi Jewish women, for instance. But inherited breast cancers account for only about 7 percent of cases, so researchers have been searching for ways to determine who may be at risk among those who do not carry the BRCA1 mutation. For women in this group who develop breast cancer, the key question is why?

Enter the WWOX gene, a tumor suppressor that lives in fragile sites in the DNA that are most susceptible to cell damage. Seewaldt and Aqeilan have embarked on a series of new studies — a continuation of earlier studies supported by a Barron grant bestowed in the program’s inaugural year — to further investigate the relationship between WWOX genes and TNBCs.

They have preliminary evidence that loss of WWOX expression is associated with advanced stages of TNBC and that re-expression of WWOX suppresses cancer growth. So they are combing data to determine the frequency of this damaged gene in women who are at high risk but who do not carry the BRCA1 mutation. Additionally, they are running clinical trials to see if a common diabetes prevention drug called metformin will help increase WWOX levels in the cells and act as a cancer prevention agent.

“Rami has done some of the basic biology studies and studies in mice, and these are still continuing,” said Seewaldt. “We also have a big cohort at Duke University from which we’ve collected samples over ten years, and we’re waiting to see what the frequency of WWOX loss is in that cohort and whether WWOX loss is predictive of breast cancer risk.”

Beyond that, Seewaldt and Aqeilan are enthusiastic about the potential to determine connections between the WWOX gene and environmental impact. “There are all kinds of different ways to cause damage within the body,” said Seewaldt. “Most of the time the body is able to shrug this off. But sometimes cancers develop as a result of exposure to environmental carcinogens — you live by a freeway and you’re bombarded by pollution, you eat a lot of food with pesticide in it, your water is contaminated, or you get exposed to hormone-containing beauty care products.”

“What we’re learning about the WWOX gene,” she went on to say, “is that it’s not only associated with triple-negative breast cancer, it may also act as an environmental sensor. It’s always been suspected that there’s a link between environmental exposures and the development of breast cancer, but nobody’s been able to find it very convincingly. This is probably one of the first links that ties these things together.”

Seewaldt and Aqeilan are not only colleagues, they’re also friends. Seewaldt travels to Israel three or four times a year, and the Israeli scientist’s family stayed at Seewaldt’s house on a recent visit to the States. “When the two families are sitting around, we talk about how the kids are doing and everything, but we spend a lot of time talking about science,” said Seewaldt, who next goes back to Israel in August.

Seewaldt credited the Barron grant with allowing the two of them to translate Aqeilan’s preliminary work with cell lines and mice to clinical purposes so that they can apply the detailed molecular models he’s created to large groups of human patients suffering from breast cancer.

“We’re able to enhance the value of Rami’s exceptional research for people not just in the U.S. or even in the Middle East but worldwide,” Seewaldt said. “And it’s the Barron funding that has made this all possible. It’s incredibly cost effective with amazing results and the potential for a huge impact.”