Environmental Factor, June 2011, National Institute of Environmental Health Sciences
Liu discusses a systems biology approach to breast cancer
By Archana Dhasarathy
Liu describes his work as spanning cancer biology, genomics, human genetics, and molecular epidemiology. (Photo courtesy of Steve McCaw)
NIEHS Laboratory of Molecular Genetics Principal Investigator Mike Resnick, Ph.D., was one of several scientists who asked questions following the talk. (Photo courtesy of Steve McCaw)
Paules watched and often smiled as Liu joked as he answered queries from the audience. (Photo courtesy of Steve McCaw)
Edison Liu, M.D.,(http://www.gis.a-star.edu.sg/internet/site/investigator/investigator.php?user_id=14) outlined a novel integrative genomics and systems biology approach to breast cancer during his 2010-2011 NIEHS Distinguished Lecture Series presentation April 22, titled "Systems reconstruction of the ER-alpha network: From bench to the clinic." NIEHS Environmental Stress and Cancer Group Principal Investigator Rick Paules, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/ltp/esc/index.cfm), hosted the talk by Liu, who is currently executive director of the Genome Institute of Singapore(http://www.gis.a-star.edu.sg/internet/site/index.php) and president of the Human Genome Organisation (HUGO)(http://www.hugo-international.org/) .
"One thing that the genome has taught us is that it is really complex," said Liu. He stressed the need to embrace this complexity and resolve biological mechanisms by a deeper understanding of each component and its nodes of interaction.
Mapping estrogen receptor DNA binding sites in the genome
Estrogen receptor alpha (ER-alpha) is a key molecule in breast cancer, and loss of ER-alpha is associated with poor prognosis. In the presence of estrogenic compounds like estradiol, ER-alpha binds to distinct regions of DNA called estrogen response elements (EREs) and helps to turn genes on or off. Using genome-wide techniques with the MCF-7 breast cancer cell line enabled Liu's group to identify the locations of EREs, and map them to genes that are regulated by estrogen. The researchers determined that many of these EREs are located near genes that are significantly associated with breast cancer biology. Further, they determined that approximately 98 percent of these EREs have sequences that energetically favor ER-alpha binding.
When Liu and his colleagues examined the motifs adjacent to the ER-alpha binding sites, they found the presence of two other transcription factors, GATA3 and FOXA1, which can co-occupy some of the same binding sites as ER-alpha. The best induction of cell growth and gene activation results when all three factors are present around the same binding site. Thus, the presence of these co-factors helped to organize the genome for optimal binding.
The importance of DNA loops in gene regulation
The mapping results revealed that while many EREs were located as expected near the start sites of genes, approximately 40 percent were actually in intragenic regions, suggesting different mechanisms of action. The researchers also found that even when an ERE was located away from the start of a gene, it was still associated with RNA polymerase, which is necessary for genes to be actively transcribed. This association suggested to them that an alternative mechanism could help bring both the ER-alpha and RNA polymerase that are bound to a distal site in close proximity to the start site of the gene, and allow transcription. Hence, a major finding of their research was that ER-alpha could influence gene expression across distances of up to 100 kilobases or more.
Liu's group hypothesized that the formation of a DNA loop provides a sort of DNA cage for factors, such as ER-alpha and RNA polymerase, to bring them all together and allow gene transcription. DNA acts as a catalyst to bring different factors together, maximizing transcription factor usage. Many sites could consequently be covered by the limited number of transcription factors in a cell, which maximizes efficiency of gene regulation.
ER-alpha and breast cancer susceptibility
Liu then asked whether variations in ER-alpha signaling could influence breast cancer susceptibility. Global tests of genetic association between SNPs in the ER-alpha pathway and breast or endometrial cancer identified the aromatase SNP as significant, pointing to the potential of using aromatase inhibitors in therapy.
As Liu ended his talk, he told the audience, "God made ER-alpha signaling for reproduction, not for oncologists to understand breast cancer susceptibility." The regulation of ER-alpha is highly controlled, so that even slight perturbations can lead to evolutionary demise, while individual variations can enhance survival of the species, he concluded.
(Archana Dhasarathy, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Carcinogenesis Eukaryotic Transcriptional Regulation Group.)