Researchers Zero In On Estrogen's Role In Breast-cancer Cell Growth

In a paper that will appear in the Sept. 13 issue of the Proceedingsof the National Academy of Sciences, the scientists report that humanbreast-cancer cells exposed to estrogen in their laboratory showed adramatic reduction in numbers of a crucial nuclear receptorcorepressor, a protein known as N-CoR (pronounced "en CORE"). They alsofound that the anti-estrogen drug tamoxifen, often used inbreast-cancer treatments, encouraged N-CoR recovery, a beneficialactivity. The paper was published online last week.

"Because estrogen has the ability to reduce the levels ofN-CoR, estrogen then can promote the proliferation and progression ofbreast cancer, because the balance of co-activators and co-repressorsinvolved in normal gene transcription is altered," said Benita S.Katzenellenbogen, a Swanlund Professor of Cell and DevelopmentalBiology at Illinois. She also is a professor of molecular andintegrative physiology.

The findings may have sweeping implications, saidKatzenellenbogen and lead author Jonna Frasor, a postdoctoralresearcher who joins the faculty of the department of physiology andbiophysics in the U. of I. College of Medicine at Chicago this month.

For one, the mechanisms at play could explain at least some ofthe mixed results seen in women using estrogen and progesterone inhormone therapy, said Katzenellenbogen, who also is a professor in theU. 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 ofN-CoR followed an up regulation of the ubiquitin ligase Siah2, anenzyme that targets certain proteins for degradation, Frasor said.

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

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

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

"Eventually," Katzenellenbogen said, "understanding more of themechanisms involved could lead to the development of other relatedagents that might reduce some of the unwanted side effects oftamoxifen, such as stimulation of the uterus."

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

The National Institutes of Health and the Breast Cancer Research Foundation funded the research.