A Perfect Union

Roughly 5 to 10 percent of breast cancer diagnoses are a direct result of an inherited mutation on the BRCA1/BRCA2 genes. But what is causing the other 90 percent?

Donato Romagnolo, PhD, MSc, and Ornella Selmin, PhD, are investigating a potentially groundbreaking genetic marker that could lead to more targeted therapies for previously untreatable breast cancer cases.

“We want to figure out what could possibly be responsible for the large percentage of breast cancer cases where patients have no family history of the disease but have lower or no detectable BRCA1,” Dr. Romagnolo said.

The BRCA1/BRCA2 mutation made headlines worldwide when actress Angelina Jolie wrote about her experiences with her inherited genetic condition in 2013. Yet one thing nearly all breast cancer cases have in common is reduced expression in these genes, even if there is no inherited mutation or familial history with breast cancer.

Drs. Romagnolo and Selmin believe that the common link between these non-inherited breast cancer cases lies within the aryl hydrocarbon receptor (AhR), a gene that has been shown to repress BRCA1 expression when it encounters environmental pollution, a high-fat diet, or prolonged exposure to ultra-violet rays.

The roots of this study date back to the mid-1980s, when these two research scientists fell in love and got married in 1985.

The husband-and-wife duo eventually made their way to the National institute of Environmental Health Sciences. Dr. Romagnolo was a nutritionist studying the BRCA1 gene, while Dr. Selmin was a molecular biologist researching AhR.
“it was a perfect union,” Dr. Romagnolo said.

They each arrived at the University of Arizona Cancer Center in 1997 and began researching the links between AhR and breast cancer with their first successfully funded grant in 1999 through the US Department of Defense (DoD), which established the Breast Cancer Research Program in 1992 to promote innovative research focused on eradicating breast cancer.

Drs. Romagnolo and Selmin hold faculty appointments in the Department of Nutritional Sciences, College and Agriculture of Life Sciences and share a laboratory at the University of Arizona Cancer Center.

Drs. Romagnolo and Selmin are among the only researchers investigating this potential link. Earlier this year, their research received the highly sought-after idea Expansion Award — a three-year, $560,000 grant to assist Dr. Romagnolo’s lab with setting up protocols and genetic models for the next phase of this study.

The DoD received more than 130 applications for idea Expansion Awards, but issued only eight awards. impact is the most important aspect of the idea Expansion Award. Research that has the potential to significantly accelerate the eradication of breast cancer is considered to have high impact.

“We’re still not sure if AhR is the cause or the effect — whether it’s driving the lower BRCA1 expression, or if it’s simply a passenger in a larger, more complex series of events,” Dr. Romagnolo said. “But we do know AhR is involved.”
The ultimate goal of this study is to determine whether AhR can serve as a genetic marker to develop the first targeted therapies for triple-negative breast cancer— providing safer, more effective treatments for a disease that claims more than 40,000 lives each year.

Last year, Drs. Romagnolo and Selmin (along with research technician Jamie L. Borg, and former Nutritional Sciences doctoral student Andreas Papoutsis) published a paper in the journal Molecular Carcinogenesis, suggesting that these external environmental and dietary factors in pregnant women may have an impact on future breast cancer risk for the offspring, as well.

“We’re on the cusp of a major discovery,” Dr. Romagnolo said. “We know the gene’s blueprint, and we know the risk factors. The next step is to turn these findings into life-saving therapies.”