Why do estrogen-dependent breast-cancer cells grow and spread rapidly?

Researchers at the University of Illinois at Urbana-Champaign say it may be because estrogen virtually eliminates levels of a vitally important regulatory protein.

In a paper that will appear in the Sept. 13 issue of the Proceedings of the National Academy of Sciences, the scientists report that human breast-cancer cells exposed to estrogen in their laboratory showed a dramatic reduction in numbers of a crucial nuclear receptor corepressor, a protein known as N-CoR (pronounced "en CORE"). They also found that the anti-estrogen drug tamoxifen, often used in breast-cancer treatments, encouraged N-CoR recovery, a beneficial activity. The paper was published online last week.

"Because estrogen has the ability to reduce the levels of N-CoR, estrogen then can promote the proliferation and progression of breast cancer, because the balance of co-activators and co-repressors involved in normal gene transcription is altered," said Benita S. Katzenellenbogen, a Swanlund Professor of Cell and Developmental Biology at Illinois. She also is a professor of molecular and integrative physiology.

The findings may have sweeping implications, said Katzenellenbogen and lead author Jonna Frasor, a postdoctoral researcher who joins the faculty of the department of physiology and biophysics in the U. of I. College of Medicine at Chicago this month.

For one, the mechanisms at play could explain at least some of the mixed results seen in women using estrogen and progesterone in hormone therapy, said Katzenellenbogen, who also is a professor in the U. of I. College of Medicine at Urbana-Champaign.

While numbers of N-CoR proteins fell to 20 percent of normal, the level of N-CoR's messenger RNA went untouched. The reduction of N-CoR followed an up regulation of the ubiquitin ligase Siah2, an enzyme that targets certain proteins for degradation, Frasor said.

"Here we had an effect on the level of the N-CoR protein without affecting the level of N-CoR mRNA," Katzenellenbogen said. "This is the result of the initial effect of estrogen on gene expression, which was to up regulate the mRNA levels for a ubiquitin ligase. So by changing the level of this ligase, it had a dramatic effect on the level of N-CoR protein without affecting gene expression for N-CoR itself."

This "secondary effect" may have broad implications for other important cellular activities, the researchers theorize. Reductions in N-CoR over time also could promote cancer development in other sites, such as the uterus, and could adversely affect the desired activities of vitamin D, retinoid and thyroid receptors, Katzenellenbogen said.

The study sheds light on the impact of estrogen on certain cells, as well as how tamoxifen works as an anti-estrogen to facilitate recovery of N-CoR, she and Frasor said.

"Eventually," Katzenellenbogen said, "understanding more of the mechanisms involved could lead to the development of other related agents that might reduce some of the unwanted side effects of tamoxifen, such as stimulation of the uterus."

In addition to Katzenellenbogen and Frasor, Jeanne M. Danes, a researcher in the department of molecular and integrative physiology, and doctoral student Cory C. Funk were co-authors of the study.