Researchers Zero
in on Estrogen’s Role in Breast Cancer Cell Growth
Behind the Cancer Headlines®
Why do estrogen-dependent breast-cancer cells grow and
spread rapidly? Researchers at the
In a paper published in 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.
"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 professor of Cell and
Developmental Biology at
The findings may have sweeping implications, said Katzenellenbogen and lead author Jonna
Frasor, a postdoctoral researcher at the department
of physiology and biophysics in the U. of I. College of Medicine at
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.
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 added.
"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."
SOURCES:
Proceedings of the