In the Loop

Breast cancer cells regulate multiple genes in response to estrogen-like compounds

Tim HM HuangCancer researchers at the OSUCCC – James have discovered a type of gene regulation and DNA behavior in breast cancer cells that may offer insight about environmental exposure to estrogen-like compounds.

The study provides the first evidence that cells can regulate many genes at once by looping their DNA, contributing to cancer when this process goes awry. This regulation, discovered in breast cancer cells as a response to estrogen, resulted in the silencing of 14 genes at once.

Tim H.-M. Huang, PhD, professor of Molecular Virology, Immunology and Medical Genetics, and Pei-Yin Hsu, a visiting scholar in Huang’s lab, located the DNA looping event in a breast cancer cell line gene cluster at chromosome region 16p11.2. They validated the finding using normal human breast epithelial cells and two animal models.

They also used the normal-cell model to determine if long-term exposure to nine estrogen-like chemicals can initiate gene silencing through this mechanism. These chemicals included diethylstilbestrol, two thalates and bisphenol A (BPA).

The suppressive effects varied in normal cells, but when investigators exposed rats to BPA for 21 days, they found concurrent suppression of 10 genes comparable to those located at 16p11.2. Huang says this suggests that continuous exposure to estrogen-like compounds might lead to permanent silencing of genes in this conserved cluster.

In healthy breast epithelial cells, 14 gene regulatory sites joined to form a temporary transcription site, Huang says. “But in breast cancer cells, there is no coordinated transcription site pairing, the DNA loops become tangled and the entire gene complex shuts down in a dead knot.”

In some cases, he adds, this multi-gene regulatory mechanism can increase gene expression and oncogenic activity, further contributing to cancer.

“We offer a new concept in this paper for the collective regulation of gene transcription,” says first author Hsu, who identified the loop structures and their significance. “We found that in normal breast cells, DNA looping is more flexible and brings different promoters together temporarily. But in cancer, this complex just locks up and causes long-term suppression.”

For a demonstration of DNA looping, visit: http://www.youtube.com/watch?v=4y0e6oumqdo.

Published in the journal Genome Research.

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