Breast cancer is cancer of breast tissue.
Worldwide, it is the most common form of cancer in females, affecting approximately 1 out of 11-12 women at some stage of their life in the Western world.
Although significant efforts are made to achieve early detection and effective treatment, about 20% of all women with breast cancer will die from the disease, and it is the second most common cause of cancer deaths in women.
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Breast cancer runs in families; however, genetic predisposition (such as being BRCA1 or BRCA2 mutation carriers) explains only a portion of this observation. Epigenetic changes (modifications in the genome that alter gene expression but do not affect the DNA sequence per se) have been shown to also play a role in breast cancer risk.
Researchers from the Columbia University Medical Center in New York have now examined whether a specific epigenetic modification (more specifically, methylation of the DNA) can be associated to breast cancer family history in unaffected women from high-risk breast cancer families. This important work suggests that the levels of DNA methylation in white blood cells from cancer-free women could be one of the factors playing a role in the clustering of breast cancer in families with extensive cancer histories within its members.
Age is a key risk factor for breast cancer. A recent study by researchers from the Dartmouth-Hitchcock Norris Cotton Cancer Center (NCCC), "Age-related DNA methylation in normal breast tissue and its relationship with invasive breast tumor methylation," examines the connection between cancer and the aging process to see if epigenetic DNA alterations might contribute to age-related increases in breast cancer risk.
Epigenetics is the study of changes in gene function such as gene expression or gene expression potential -- heritable changes passed during cell division -- that occur without changes in DNA sequence. The study is available online and will appear in the February 2014 issue ofEpigenetics.
"In this work we are trying to gain a clearer understanding of the relationship between aging and epigenetic changes in cancer-free breast tissue," said Brock C. Christensen, PhD, assistant professor of Community and Family Medicine and of Pharmacology and Toxicology at Geisel and a researcher at the Norris Cotton Cancer Center. "This will help focus our search for early age-related molecular events that may contribute to increased risk of developing breast cancer."
The NCCC researchers analyzed publicly available genome-wide DNA methylation data from disease-free breast tissues and identified consistent methylation alterations associated with aging across multiple groups of subjects. (DNA methylation is an epigenetic mark that can occur on cytosine residues that are followed by guanine, also known as CpG dinucleotides, and contribute to regulation of gene expression.) They then compared levels of methylation in normal tissues to breast tumor tissues and confirmed that age-related changes present in normal breast tissues were present and more prominently altered in breast tumors. The NCCC study suggests that there may be common genomic regions that are particularly susceptible to age-related changes in DNA methylation over time in disease-free breast tissue and contribute to development of cancer.
"Our approach here is somewhat distinct from conventional cancer epigenome-wide studies in that we are focused first on characterizing age-related patterns of DNA methylation in disease-free tissue rather than tumors," said Christensen. "The profound changes in DNA methylation observed in breast tumors compared with disease-free breasts make it difficult to determine which DNA methylation alterations occur early in carcinogenesis. We think that our approach is one way to step toward identifying early molecular changes that truly contribute to tumor formation."
The NCCC researchers are currently working on a larger study of DNA methylation in cancer-free breast tissues where they hope to more completely characterize age-related methylation in normal breast tissue. They will also assess whether other important breast cancer risk modifiers (such as family history of disease and reproductive history) are related to DNA methylation patterns in normal breast tissue.
The above story is based on materials provided by Norris Cotton Cancer CenterDartmouth-Hitchcock Medical Center.
BRCA 1 breast cancer gene plays a protective role against the development of metabolic disease
The gene known to be associated with breast cancer susceptibility, BRCA 1, plays a critical role in the normal metabolic function of skeletal muscle, according to a new study led by University of Maryland School of Public Health researchers. Dr. Espen Spangenburg, associate professor of kinesiology, and his laboratory team are the first to identify that the BRCA1 protein is expressed in the skeletal muscle of both mice and humans, and that it plays a key role in fat storage, insulin response and mitochondrial function in skeletal muscle cells. The research is published in the Journal of Lipid Research.
"Our findings suggest that certain mutations in the BRCA1 gene may put people at increased risk for metabolic diseases like obesity and type 2 diabetes," said Dr. Spangenburg. "Without BRCA1, muscle cells store excess fat and start to look diabetic. We believe that the significance of the BRCA1 gene goes well beyond breast cancer risk."
Dr. Spangenburg and colleagues, including researchers from the University of Maryland School of Medicine, Brigham Young University, Karolinska Institutet in Sweden, and East Carolina University, found that the BRCA1 protein exists in both mouse and in human skeletal muscle. This is the first evidence since the discovery of BRCA1 in 1994 that the gene is expressed in human muscle cells.
They further established that the protein produced by the BRCA 1 gene binds with a protein known to play an important role in the metabolism of fat in muscle cells known as Acetyl-CoA carboxylase or ACC. After a period of exercise, the BRCA 1 protein binds to ACC, which helps "turns it off." This deactivation of ACC encourages the utilization of fatty acids by the muscle.
Once they established that the two proteins complex together, they sought to answer if BRCA1 plays a critical role in regulating muscle metabolic function. To do so, they "knocked out" the gene so that it was no longer being expressed in the muscle cells cultured from healthy, active and lean female subjects. This was done using shRNA technology specific for BRCA1 in human myotubes (skeletal muscle fiber cells).
The result was that the muscle cells started to look diseased. The removal of BRCA1 from the cells, which simulated what could happen in the cells of a person with a BRCA1 mutation, resulted in increased lipid storage, decreased insulin signaling, reduced mitochondrial function and increased oxidative stress. These are all key risk factors for the development of metabolic diseases, such as obesity, type 2 diabetes and cardiovascular disease.
"Our findings make it clear that BRCA1 plays a protective role against the development of metabolic disease," Dr. Spangenburg explains. "This gene needs to be there, and should be considered a target to consider in the treatment of type 2 diabetes and/or obesity."
Breast cancer statistics are presented here.
- In 2010, 49,564 women and 397 men in the UK were diagnosed with invasive breast cancer.
- In 2011, there were 11,684 female and 78 male deaths from invasive breast cancer in the UK.
- In 2005-2009, 85.1% of adult female breast cancer patients in England survived their cancer for five years or more.
- In 2010, 5,765 women and 26 men in the UK were diagnosed with in situ breast carcinoma.
Women with mutations in the BRCA1 gene are at high risk for breast and ovarian cancer, and there are currently no drugs proven to reduce their cancer risk.
Now, early research suggests that existing drugs, already approved to treat other conditions, may help prevent breast cancer in these women, although more research is needed to prove this.
One drug, called benserazide, is currently used for Parkinson's disease, and in studies it reduced the formation of breast tumors in mice that had been implanted with cancer cells containing the BRCA1 gene mutation. All of the mice that did not receive the drug developed breast tumors, but 40 percent of mice given the drug were tumor-free, said study researcher Elizabeth Alli, of Stanford University School of Medicine.
Some studies show that women with mutations in the BRCA1 gene have a 50 to 70 percent chance of getting breast cancer by age 70, compared with a 12 percent lifetime risk for the average American woman. Last year, actress Angelina Jolie announced she had undergone a double mastectomy to prevent breast cancerbecause she has a BRCA1 gene mutation.
Two drugs, tamoxifen and raloxifene, are already approved to prevent breast cancer, but there's little information about how well they work for women with BRCA1 gene mutations. Both drugs work by blocking the action of estrogen on breast cells; the hormone can fuel the growth of certain types of breast cancer.
"The data out there for the efficacy of these drugs [among carries of BRCA1 mutations] is controversial, and inconsistent," Alli said. "So really it'd be ideal to identify new drugs that are more effective for this population."
The BRCA1 gene is involved in repairing damaged DNA — a critical function, because damage to DNA can lead to cancer. Mutations in the BRCA1 gene increase the risk of cancer because they impair this repair process.
Benserazide, and possibly other drugs, may work to prevent breast cancer from BRCA1 mutations by restoring cells' ability to perform one type of DNA repair, the researchers said.
Alli noted that tamoxifen also increases the risk of endometrial cancer (cancer of the uterus lining), and for some women, this risk may outweigh the drug's benefits.
The next step in the research is to see whether benserazide, or other drugs that work similarly, prevents breast cancer in mice that have been genetically engineered to have BRCA1 gene mutations.
The drug will also need to be tested in a clinical trial before researchers know whether it works in people. It's not clear how soon a trial could start after the work in mice, but it could be relatively quick because the drug is already being used in people, Alli said.
However, even after a trial begins, it can take many years to enroll enough people to complete a study, she said.
The study was presented this month at the American Association for Cancer Research meeting in San Diego.
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Younger women who are obese have a 34 percent higher risk of dying from their breast cancer, a new study finds.
Doctors have long known that being overweight or obese raises a woman’s risk of developing breast cancer, and they know it’s not especially good for women who have it, either. What’s not been clear is just how harmful it is, and whether a woman’s age or the type of cancer she has matters.
The new study, which will be presented next month at the annual meeting of the American Society of Clinical Oncology, found that obesity is only significantly dangerous for women who get breast cancer before menopause and who have the type that’s fed by the hormone estrogen.
Hongchao Pan and colleagues at Britain’s University of Oxford looked at data on 80,000 women with breast cancer. They found that for the women who were already past menopause, and those who had so-called hormone-negative breast cancer, being obese didn’t matter.
But it did for the younger women with hormone-positive breast cancer — the most common kind.
“Despite everyone knowing the truth of this, the levels of overweight and obesity in the U.S. continue to climb,” said ASCO president Dr. Clifford Hudis. “Knowing that it is a negative health factor in so many domains is not yet an effective way of changing behavior.”
More than a third of American women are obese and another third are overweight.
Fat cells produce estrogen and this may be a factor. Breast cancer is the second-leading cancer killer among U.S. women, after lung cancer. Every year it's diagnosed in 200,000 women and a few men, and kills around 40,000.