Estrogen may be linked to several causes of breast cancer, according to a new study by researchers at the University. While the hormone has long been known to promote breast cancer by causing breast cancer cells to grow, researchers at the University have found that estrogen also works to shield cancer cells from attack by the immune system.

“Most cancer cells are recognized by the immune system,” said David Shapiro, professor of biochemistry and leader of the study. “The immune system then releases proteins called granzymes that attack and kill the cancer cells.”

However, some cells contain a protein called a granzyme inhibitor that attaches to the granzymes and prevents them from working, Shapiro said. High levels of the granzyme inhibitor may contribute to the lethality of some cancers.

Shapiro led a team of researchers who found that the granzyme inhibitor is what allows cells to escape attack by the immune system. In some breast cancer cells, when estrogen binds to an estrogen receptor protein, this forms the granzyme inhibitor.

It only takes low levels of estrogen to jump-start this process. Xinguo Jiang, graduate student in molecular and integrative physics, discovered that when breast cancer cells containing high levels of estrogen receptor protein are exposed to low levels of estrogen, they produce large amounts of the granzyme inhibitor and become highly resistant to attack by the immune system.

“There are two things we can do with this finding,” Shapiro said. “As researchers identify small molecules for further testing against estrogen action in breast cancer, we can now test to see whether they can prevent estrogen from causing production of this protein that prevents immune cells from killing cancer cells.”

More can be learned about potential drugs as more is learned about the protein.

“It may be possible to identify potential drugs that work by blocking the action of the protein after it has been made in response to estrogen,” Shapiro said. “These drugs would restore the sensitivity of the breast cancer cells to killing by immune cells.”

As every cancer is unique, and no single protein is responsible for all cancers, Shapiro said he wants to determine whether this protein is prevalent in a large percentage of breast cancers, or if it only affects a small number of breast cancers.

The research was originally intended to develop a rapid method for testing tens of thousands of different chemicals, and to identify those that could block this estrogen bonding process, Shapiro said. The chemicals that worked in the rapid screening are then tested in more complex evaluations that are directly related to the way estrogen works to promote breast cancer.

One test is for a chemical to block the estrogen-based growth of breast cancer cells, Shapiro said. Based on the tests showing the shielding effects of estrogen, researchers tried to use these concepts to develop further tests. This led to the finding of the granzyme inhibitor.

“This is an example of how a basic research study can have important and unanticipated implications for understanding a disease such as breast cancer,” Shapiro said.