Potential New Drug Targets Against Hormone-dependent Breast Cancer Identified

"These two receptors, called EP2 and EP4, form key links in a biochemical pathway that boosts estrogen production in fat and breast cancer cells — this, in turn, may increase a woman's risk for developing hormone receptor-positive breast cancer. Finding ways to interrupt this pathway in a manner that causes few side effects is the ultimate goal of this research," explains the study's senior author Dr. Andrew Dannenberg, director of the newly established Cancer Center at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, and the Henry R. Erle, M.D.–Roberts Family Professor of Medicine at Weill Cornell Medical College.*

About 75 percent of all breast malignancies are "estrogen receptor-positive," meaning that their cells carry receptors attuned to estrogen. In the presence of the hormone, these cancer cells will divide and grow. For this reason, anti-estrogen drugs such as tamoxifen and aromatase inhibitors have come to the forefront in the fight against hormone-dependent breast cancer.

"Aromatase, an enzyme, boosts the amount of estrogen made by both fat cells and breast cancer cells," explains the study's lead author, Dr. Kotha Subbaramaiah, recently appointed the Jack Fishman Associate Professor of Cancer Prevention at Weill Cornell. "Cancer researchers have for years been exploring the pathway by which aromatase is regulated. We know that if you reduce aromatase activity that you also reduce levels of cancer-causing estrogen in breast tissues."

In 2006, researchers led by Dr. Dannenberg discovered that cyclooxygenase (COX) protein-derived prostaglandin E2 (PGE2) could turn on the gene that expresses aromatase. More recently, the healthy form of the BRCA1 tumor-suppressor gene was found to quiet the aromatase gene — performing its duty in keeping breast cancer risk low.

"Maintaining this BRCA1-aromatase relationship in a healthy balance may help to keep patients free of hormone-dependent breast cancer," Dr. Dannenberg explains.

Studies have shown that use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) can also dampen PGE2 production and aromatase activity. COX-2 inhibitors (which include Vioxx and Celebrex) may do the same. However, these drugs also suppress a prostanoid that helps protect the heart, and in 2004 Vioxx was withdrawn from the market due to an excess of cardiovascular events noted in long-term users.

"So, we are always looking for other points in the prostaglandin — aromatase — estrogen pathway that can shield women from breast cancer without raising risks in other areas," Dr. Dannenberg says.

That's one of the reasons the results of the new study are intriguing. Using experiments conducted in cell culture and in the mammary tissues of mice, the Weill Cornell team discovered that two cellular receptors — EP2 and EP4 — switch on a complex biochemical pathway that activates the aromatase gene.

"It appears that PGE2 binds to these receptors and that this causes a downregulation of BRCA1," Dr. Subbaramaiah says. "As we already know, less BRCA1 means more aromatase activity to produce estrogen, and that could mean a higher risk for estrogen-receptor positive cancer."

The team found that EP2 and EP4 performed in this way in both adipocytes (fat cells) and in breast cancer cells. This could be important for both the development and growth of breast cancer.

"We also validated the presence of this pathway in an animal model, the first time that's ever been done," Dr. Dannenberg notes.

The finding has many implications going forward. First of all, it adds valuable new information to the study of hormone-dependent breast cancer generally. "Pinpointing the role of these receptors is like adding two important new parts to the tumor's 'instruction kit.' You have to understand all the players involved if you hope to uncover weaknesses to fight or prevent the disease," Dr. Dannenberg says.

Finally, the receptors offer brand new targets for pharmaceutical research. "In fact, drugs that work against EP2 and EP4 ('antagonists') are already in development by pharmaceutical companies," Dr. Subbaramaiah says. "Our confirmation of the receptors' key role in regulating aromatase activity supports the further development of this form of targeted therapy."

*These findings were published recently in the online edition of the Journal of Biological Chemistry. Co-researchers include Dr. Clifford Hudis of Memorial Sloan-Kettering Cancer Center, New York City; as well as Dr. Sung-Hee Chang and Dr. Timothy Hla of the University of Connecticut Health Center, Farmington.

This work was supported by the Breast Cancer Research Foundation, the U.S. National Institutes of Health, the Botwinick-Wolfensohn Foundation, and the Center for Cancer Prevention Research.