How estrogen turns on genes in breast cancer

USC (US) — New research has determined the key process by which estrogen, the female sex hormone, activates genes in breast cancer cells, a finding that could eventually lead to new treatments for the disease.

Researchers found that a protein, TIP60, recognizes when a common chemical process called methylation occurs in chromatin, the material that enfolds all genes.

Methylation controls how genes are folded in the complex structure of chromatin, which determines whether the genes are active or inactive.


After recognizing the methylation signal, researchers discovered TIP60 then binds to the signal, connecting TIP60 to the chromatin and changing the chromatin’s structure—which helps to activate the gene. The methylation that TIP60 recognizes is generated by another protein, MLL1.

“It’s like when you’re in your car and come to a red light,” says Michael Stallcup, professor of biochemistry and molecular biology at University of Southern California.

“The light doesn’t make you stop, but it is a signal that you have to interpret and then decide to stop. In this case, the methylation modification that TIP60 recognizes is one of those signals, and then TIP60 acts on that signal.”

Published online in the journal Nature Structural & Molecular Biology, the findings build upon previous work of Stallcup’s lab that revealed that the methylation of chromatin and other proteins plays several important roles in controlling the activities of genes.

While the recent findings are significant, Stallcup stressed that there is much more to be discovered.

“We want to understand more about other steps in the process of gene activation,” Stallcup says. “In particular, we’re interested in the function of the MLL1 protein because we think it plays a key role in controlling chromatin structure and folding, which we think is critical for activation of genes by estrogen.”

While estrogen regulates just a few hundred of the tens of thousands of genes in every human cell, the research has broader implications, Stallcup says.

“While the process we’re studying is the regulation of gene activity by estrogen, the findings have potentially global significance,because the methylation modification of chromatin that TIP60 recognizes is found in all active and potentially active genes in human cells.”

Kwang Won Jeong, a postdoctoral student in Stallcup’s lab, is the paper’s first author.

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