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Under the Microscope: A Bold Push to Beat Breast Cancer

Despite great progress in diagnosis and treatment, breast cancer is still second only to lung cancer for cancer deaths among women. Innovative research is needed to develop targeted new treatments, understand who is most vulnerable to this complex cancer and develop the best care for breast cancer survivors.

The V Foundation’s more than $30 million in breast cancer research grants supports young investigators taking unique approaches to studying breast cancer, work that aims to boost enrollment in important clinical trials, and research bringing new treatments and diagnosis strategies from the lab to the clinic. A new set of V Foundation grants will focus on breast cancer survivors, of which there are more than 3.5 million in the U.S., by examining issues such as how to decrease long-term complications from treatments.

Understanding an aggressive cancer

With early career funding from the V Foundation, Qing Zhang, PhD, a researcher at the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, is making important new discoveries about triple negative breast cancer that are already revealing potential new leads for fighting this aggressive and hard-to-treat cancer.

Breast cancers are considered triple negative when they lack (are negative for) receptors for estrogen or progesterone and don’t make excess amounts of a protein called HER2. The absence of hormone receptors means these tumors don’t respond to hormone-based therapies that are effective for other breast cancers.

Postdoctoral fellow Giada Zurlo, rotation graduate student Andrew Truong, Qing Zhang and research technician Adam Robinson from the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.

Zhang and his research team are particularly focused on the oxygen sensor EGLN2, an enzyme found in high levels in triple negative breast cancer. “We want to understand how this enzyme allows a cancer cell to sense oxygenation and then program its cellular pathways in a way that allows tumor cells to survive under a harsh, low-oxygen environment,” he said. “Very few scientists are studying this pathway, which could reveal new targets for cancer therapy.”

Zhang recently received funding from the American Cancer Society and the Mary K Foundation to expand his research on EGLN2. His work was also recognized with the prestigious Jefferson-Pilot Fellowship in Academic Medicine from the UNC School of Medicine.

“The early career development provided by the V Foundation allows the pursuit of risky but bold ideas,” said Zhang. “It has been key in building a strong foundation for grant support from other institutions.”

Slowing tumor progression

The researchers began by working to understand how the EGLN2 oxygen sensor affects triple negative breast cancer. So far, they have found that mice with triple negative breast cancer and depleted levels of the EGLN2 oxygen sensor live longer because their tumors progress more slowly. Zhang’s team also discovered that EGLN2 is highly expressed in triple negative breast cancer not because of increased gene expression but because of a mechanism that makes the sensor protein highly stable in these tumors.

Armed with this new information, Zhang and his team searched for compounds that might inhibit the enzyme. “Our preliminary results from studies in cultured cells have revealed several compounds that specifically inhibit EGLN2 and thus look promising in terms of inhibiting breast cancer cell growth and potential metastasis,” said Zhang.

The researchers are now working to determine whether the compounds they have found will be toxic to healthy cells and can be made strong enough to enter breast cancer cells found inside a tumor. Because EGLN2 is not only important in triple negative breast cancers, but also plays a role in estrogen-receptor-positive breast cancer, the inhibitors could also prove useful for treating other breast cancers.