Researchers Study Receptors' Role in Estrogen Production

With about 1 million new cases of breast cancer diagnosed each year, the disease poses a formidable challenge to researchers. But scientists are nevertheless making considerable headway. In a recent study, doctors Andrew Dannenberg and Kotha Subbaramaiah of Weill Cornell Medical College identified the mechanisms by which two receptor proteins, EP2 and EP4, are involved in estrogen production. Estrogen has long been known to play a role in estrogen receptor-positive breast cancer, which makes up 75 percent of breast cancer cases.

Dannenberg and Subbaramaiah specifically looked at estrogen production regulated by aromatase, a protein whose activity increases in ER-positive breast cancer cells.

The receptors came into the picture by way of their interaction with a fatty acid derivative, prostaglandin E2, which was previously shown to regulate aromatase levels in cells. The receptors’ role on aromatase levels was the missing link in the picture until now. Thus, by uncovering the mechanisms of aromatase-dependent estrogen synthesis, the two have increased the potential of breast cancer treatment.

“The molecules that we identified as being important, the receptors known as EP2 and EP4, are potentially druggable, and there are companies interested in the development of antagonists to those particular receptors, and our data would support the potential use of those drugs in an effort to suppress breast carcinogenesis,” Dannenberg said. He added that medicines like aspirin may even be co-opted for breast cancer treatment.

“The idea that we put forward several years ago was that aspirin use would, in all likelihood, lead to a reduced level of estrogen in the breasts, which in turn would protect against hormone receptor-positive breast cancer,” he said. “And if you think about the number of women out there who are both postmenopausal and have arthritis, it’s a very large number of people out there who are taking arthritis and pain medicines, and those medicines are aspirin-like.”

The study also elucidated the relationship between aromatase and its newly identified partner — the tumor suppressor gene BRCA1.

“BRCA1 tumor suppressor gene is exquisitely sensitive to being suppressed by these proinflammatory prostaglandins, and loss of the BRCA1 gene is associated with the increase in aromatase, so it in a sense provides new information about how molecules involved in inflammation can play a role in the development of cancer,” Dannenberg said.

The two scientists emphasized, however, that this study, like all others in basic research, really focused on the mechanisms of the estrogen production and does not directly or immediately lead to any new cancer therapies. The mechanisms underlying the whole system are ultimately necessary to understand for such treatments.

“Once you understand a fundamental mechanism as detailed in this paper, one can have new thoughts and new ideas about how to intervene,” Dannenberg said.

According to Subbaramaiah, future projects will continue this work in models larger than the current cells.

“We would like to translate these results in vivo and to animal models as well [to see] if any of these mechanisms apply in this case,” he said.

However, any potential treatments based on breast cancer research like this still have a long way to go.

“Giving aromatase inhibitors to premenopausal women is somewhat problematic because they may cause ovarian cysts in premenopausal women,” said Dr. Serdar Bulun of Northwestern University, who works in the same field. “Therefore, the current treatments need to be modified so that they can be administered to premenopausal women. There are a number of hurdles. However, this study provides important visions.”