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Molecular atlas provides new tool for understanding estrogen-fueled breast cancer
October 03, 2006BOSTON - Lurking in unexplored regions of the human genome are thousands of previously unknown on/off switches that may influence how the growth of breast cancer is driven by estrogen, new research by Dana-Farber Cancer Institute researchers has revealed.
In the October issue of Nature Genetics, the investigators present the first complete map of the molecular "control panels" - stretches of DNA that turn genes on and off - operated by the cells' estrogen receptor, the master regulator of cell growth in the most common form of breast cancer. The map, which includes thousands of such control regions, provides scientists with a new tool for understanding how genes are regulated, and may eventually help doctors match patients with treatments that are most likely to be effective for them and overcome the problem of resistance to current hormone therapies, the study authors say.
The estrogen receptor (ER) is an intricate protein net in the nucleus of breast cancer cells. When the receptor snares an estrogen molecule, it sets in motion a cascade of activity among genes involved in cell growth and division. In many breast tumors, cells have an unusually large number of ERs, so they proliferate rapidly in the presence of estrogen. Drugs that block the ER, such as tamoxifen and fulvestrant, are often able to stop or slow the growth of these estrogen-driven tumors.
"For the most part, the sequence of steps between the activation of the estrogen receptor and the beginning of tumor cell division has been unclear. We've known of only a handful of the portions of genes that bind to the ER - the so-called control regions that activate or deactivate the genes," says Dana-Farber's Myles Brown, MD, the senior author of the new study. "With this project we've located all of them, and found there are thousands more than were previously known." Since most genes have more than one control region, the map points to about 1,000 genes influenced, to some degree, by the ER.
The binding-site map was compiled with a novel two-step procedure called ChIP-on-chip. Researchers first used a technique called chromatin immunoprecipitation (ChIP) to purify the regions of genes that take orders from the ER. They then placed these pieces of DNA on "microarray chips" containing the entire human genome sequence. This allowed the researchers to identify all the points in the genome where binding with the ER takes place.
The researchers coined the word "cistrome" to describe the map they had produced - an atlas of all gene segments influenced by the ER. "cis" refers to a DNA segment that regulates a gene's activity in response to a signal from outside the gene (while "trans" refers to a factor that acts on DNA); and "ome" - from the Greek word for manager - refers to the full set of such segments, as "genome" refers to all the genes within human cells.
The map contains many surprises, the study authors say. For one, the majority of binding sites within the cistrome are often very far from the portions of the genes that contain the blueprints for proteins. This overturns the commonly held notion that the ER might favor sites close to the protein-coding regions of genes.
"More than 70 percent of breast cancers are ER-positive, meaning their growth is driven by estrogen," Brown says, "and the estrogen receptor is the most important target for therapy for these tumors. Knowing the complete set of ER binding sites gives us a new resource for understanding the role of estrogen in breast cancer. By identifying genes associated with the ER in breast tumors, it opens up previously unexplored regions of the genome involved in the estrogen-dependence of breast cancer."
The knowledge may one day help researchers and physicians determine which treatments are likely to work best in individual patients and restore the potency of cancer drugs to which patients have become resistant, added Brown, who is also a professor of medicine at Harvard Medical School.
Dana-Farber Cancer Institute
"For the most part, the sequence of steps between the activation of the estrogen receptor and the beginning of tumor cell division has been unclear. We've known of only a handful of the portions of genes that bind to the ER - the so-called control regions that activate or deactivate the genes," says Dana-Farber's Myles Brown, MD, the senior author of the new study. "With this project we've located all of them, and found there are thousands more than were previously known." Since most genes have more than one control region, the map points to about 1,000 genes influenced, to some degree, by the ER.
The binding-site map was compiled with a novel two-step procedure called ChIP-on-chip. Researchers first used a technique called chromatin immunoprecipitation (ChIP) to purify the regions of genes that take orders from the ER. They then placed these pieces of DNA on "microarray chips" containing the entire human genome sequence. This allowed the researchers to identify all the points in the genome where binding with the ER takes place.
The researchers coined the word "cistrome" to describe the map they had produced - an atlas of all gene segments influenced by the ER. "cis" refers to a DNA segment that regulates a gene's activity in response to a signal from outside the gene (while "trans" refers to a factor that acts on DNA); and "ome" - from the Greek word for manager - refers to the full set of such segments, as "genome" refers to all the genes within human cells.
The map contains many surprises, the study authors say. For one, the majority of binding sites within the cistrome are often very far from the portions of the genes that contain the blueprints for proteins. This overturns the commonly held notion that the ER might favor sites close to the protein-coding regions of genes.
"More than 70 percent of breast cancers are ER-positive, meaning their growth is driven by estrogen," Brown says, "and the estrogen receptor is the most important target for therapy for these tumors. Knowing the complete set of ER binding sites gives us a new resource for understanding the role of estrogen in breast cancer. By identifying genes associated with the ER in breast tumors, it opens up previously unexplored regions of the genome involved in the estrogen-dependence of breast cancer."
The knowledge may one day help researchers and physicians determine which treatments are likely to work best in individual patients and restore the potency of cancer drugs to which patients have become resistant, added Brown, who is also a professor of medicine at Harvard Medical School.
Dana-Farber Cancer Institute
Breast Cancer News and Current Breast Cancer Events RSSM. D. Anderson study finds change in HER2 status after treatment with Herceptin
Researchers at The University of Texas M. D. Anderson Cancer Center have discovered that when treated with Herceptin prior to surgery, 50 percent of HER2 positive, breast cancer patients showed no signs of disease at the time of surgery.
M. D. Anderson study finds racial disparities in radiation therapy rates for breast cancer
Black women are less likely than white women to receive radiation therapy after a lumpectomy, the standard of care for early stage breast cancer, according to a new study by researchers at The University of Texas M. D. Anderson Cancer Center.
New nano device detects immune system cell signaling
Scientists have detected previously unnoticed chemical signals that individual cells in the immune system use to communicate with each other over short distances.
CSHL scientists identify new drug target against virulent type of breast cancer
Tumor cells in a particular subset of breast cancer patients churn out too much of a protein called ErbB2 -- also often called HER2 -- which drives the cells to proliferate unchecked. Patients unlucky enough to be in this group -- about one in four -- have poorer prognoses and clinical outcomes than those who don't.
Dense tissue promotes aggressive cancers
New research may explain why breast cancer tends to be more aggressive in women with denser breast tissue. Breast cancer cells grown in dense, rigid surroundings step up their invasive activities, Vanderbilt-Ingram Cancer Center investigators report in the Sept. 9 issue of Current Biology.
Women exposed to negative life events at greater risk of breast cancer: BGU study
Happiness and optimism may play a role against breast cancer while adverse life events can increase the risk of developing the disease.
Hormone replacement therapy improves sleep, sexuality and joint pain in older women
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Positive thinking may protect against breast cancer
Feelings of happiness and optimism play a positive role against breast cancer. Research published today in the open access journal BMC Cancer suggests that while staying positive has a protective role, adverse life events such as the loss of a parent or close relative, divorce or the loss of a spouse can increase a woman's risk of developing the disease.
Anti-tumor effects are enhanced by inhibiting 2 pathways rather than 1
Two independent research groups have found that simultaneous inhibition of two signaling pathways resulted in substantially enhanced antitumor effects in mouse models of prostate and breast cancer. In an accompany commentary, Steven Grant, at Virginia Commonwealth University Health Science Center, Richmond, discusses the clinical importance of these studies and highlights some of the questions that still need to be answered.
Why a common treatment for prostate cancer ultimately fails
Some of the drugs given to many men during their fight against prostate cancer can actually spur some cancer cells to grow, researchers have found. The findings were published online this week in a pair of papers in the Proceedings of the National Academy of Sciences.
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