Posts Tagged ‘institute’

Soy supplementation adversely effects expression of breast cancer-related genes

The impact of soy consumption on breast cancer prevention and treatment is not clear although many women believe soy supplementation is beneficial based primarily on results from epidemiological studies. Moshe Shike, M.D., from the Department of Medicine at Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College in New York, NY, and colleagues conducted a randomized placebo-controlled study of the effects of soy supplementation on gene expression and markers of breast cancer risk among women diagnosed with invasive breast cancer. The study, run between 2003 and 2007 at Memorial Sloan-Kettering, enrolled a total of 140 patients who were randomized to either soy supplementation (soy protein) or placebo (milk protein), which lasted from the initial surgical consultation to the day before surgery (range=7-30 days). Tumor tissues from the diagnostic biopsy (pre-treatment) and at the time of resection (post-treatment) were then analyzed. They observed changes in several genes that promote cell cycle progression and cell proliferation among women in the soy group.

The authors conclude, “These data raise concern that soy may exert a stimulating effect on breast cancer in a subset of women.”

In an accompanying editorial, V. Craig Jordan, O.B.E., D.Sc., Ph.D., FMedSci, from the Department of Oncology at the Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, discusses how timing of soy supplementation is critical and reviews the evidence in the literature on phytoestrogens, which are contained in soy, and their known action in breast cancer. He writes, the study by Shike et al. “…illustrates the dangers of phytoestrogen consumption too soon, around menopause, but the biology of estrogen in estrogen-deprived conditions suggests that phytoestrogen could have benefit a decade after menopause.” He cautions that appropriate doses of soy and timing of consumption are critical considerations.

source : http://www.sciencedaily.com/releases/2014/09/140904183725.htm

Disparities persist in early-stage breast cancer treatment

The study, to be presented at the 2014 Breast Cancer Symposium, finds that those barriers that still exist are socio-economic, rather than medically-influenced. Meeghan Lautner, M.D., formerly a fellow at MD Anderson, now at The University of Texas San Antonio, will present the findings.

BCT for early stage breast cancer includes breast conserving surgery, followed by six weeks of radiation. It has been the accepted standard of care for early stage breast cancer since 1990 when randomized, prospective clinical trials confirmed its efficacy — leading to the National Institute of Health issuing a consensus statement. Yet, a number of patients still opt for a mastectomy. In hopes of ultimately democratizing care, it was important to look at surgical choices made by women and their association with disparities, explains Isabelle Bedrosian, M.D., associate professor, Surgical Oncology at MD Anderson.

“What’s particularly novel and most meaningful about our study is that we looked at how the landscape has changed over time,” says Bedrosian, the study’s senior author. “We hope this will help us understand where we are and are not making progress, as well as identify the barriers we need to overcome to create equity in the delivery of care for our patients.”

For the retrospective, population-based study, the MD Anderson team used the National Cancer Database, a nation-wide outcomes registry of the American College of Surgeons, the American Cancer Society and the Commission on Cancer that captures approximately 70 percent of newly-diagnosed cases of cancer in the country. They identified 727,927 women with early-stage breast cancer, all of whom were diagnosed between 1998 and 2011 and had undergone either BCT or a mastectomy.

Overall, the researchers found that BCT rates increased from 54 percent in 1998 to 59 percent in 2006, and stabilized since then. Adjusting for demographic and clinical characteristics, BCT use was more common in women: age 52-61 compared to younger or older patients; with a higher education level and median income; with private insurance, compared to those uninsured; and who were treated at an academic medical center versus a community medical center.

Geographically, BCT rates were higher in the Northeast than in the South, and in those women who lived within 17 miles of a treatment facility compared to those who lived further away.

An important question to then ask, says Bedrosian, was to compare barriers for women receiving BCT in 1998 to 2011 — and understand how have those barriers changed. The researchers found that, overall, usage of BCT has dramatically increased across all demographic and clinical characteristics, however, significant disparities related to insurance, income and distance to a treatment facility still exist.

Bedrosian is gratified to see that in the areas where physicians and the medical field can make a direct impact — such as geographic distribution and practice type — disparities have equalized over time. However, she notes that factors outside the influence of the medical field, such as insurance type, income and education, still remain. Of great interest is the insurance disparity, says Bedrosian.

“Now with healthcare exchanges providing new insurance coverage options, will we rectify the disparity and overall increase BCT use? We will have wait to see,” she says.

Bedrosian hopes that health policy makers will take note of the findings and barriers related to women receiving BCT and make appropriate changes to democratize care.

source : http://www.sciencedaily.com/releases/2014/09/140904103338.htm

‘K-to-M’ Histone Mutations: How Repressing Repressors May Drive Tissue-Specific Cancers

In 2012, investigators from multiple research institutions studying the sequence of the genome from cancer patients rocked the “chromatin world” when they independently reported that mutations in the gene that encodes histone H3.3 occurred in aggressive pediatric brain tumors. This finding was stunning, as researchers had never before associated histone mutations with any disease, much less a deadly tumor. What followed was a race by cancer researchers worldwide to discover how histone mutations might promote tumorigenesis.

Now a paper from a laboratory at the Stowers Institute of Medical Research reports the first animal model created to assess the molecular effects of two different histone H3.3 mutations in the fruit fly Drosophila. The study from a team led by Investigator Ali Shilatifard, Ph.D. published in the August 29, 2014 issue of Science, strongly suggests that these mutations actually could drive cancer and identifies interacting partners and pathways that could be targeted for the treatment of cancer.

Molecular biologists categorize these mutations as “K-to-M,” because a normal lysine residue (symbolized by K) in the protein is replaced by methionine (M) through mutations in the DNA sequence. In pediatric tumors, K-to-M mutations occurred at lysine residue 27 (K27) of histone H3.3. Researchers suggested that the presence of even a small population of these damaged proteins in the nucleus muffled a large repressor complex called PRC2. Normally, PRC2 acts as an enzyme to decorate histone lysines with one or more methyl groups, which silences gene expression by squeezing associated DNA into an impenetrable coil.

“Previously scientists knew that mutations in methylating enzymes like PRC2 occur in some cancers,” says Shilatifard. “What was surprising here was finding that mutation in one of the copies of the histone H3 gene, one of the proteins that PRC2 modifies, is associated with cancer. To figure out how that happened, we were interested in developing an in vivo model for the process in systems that we can study.”

The team first engineered a version of histone H3.3 that mimicked the K27-to-M mutation and then inserted that construct into embryonic fly tissues to produce the damaged protein in a living fruit fly. Using antibodies that recognize methylated lysines, they discovered that a dose of the mutant protein was sufficient to decrease global methylation of normal histone H3.3 proteins at K27, just as loss of the PRC2 repressor would. When the group engineered a similar K-to-M mutant at lysine 9 (K9), they saw similar results. This analysis of the H3K27 and H3K9 mutants confirmed in vivo that K-to-M mutations in histone H3.3 repress a key repressor, PRC2, but did not nail down how this happened.

“One question was whether a single amino acid change like this could alter the way histone H3.3 interacts with other proteins,” says Marc Morgan, Ph.D., a co-first author of the paper, “The mutant could be either losing or gaining something.” To determine which, the group collaborated with the Stowers Proteomics Center to compare factors binding to normal histone H3.3 versus the K-to-M mutants using mass spectrometry.

That analysis revealed that the presence of mutant histones globally dampens histone interactions with some of the usual repressor suspects. But in what Morgan calls an “Aha!” moment, they detected promiscuous association of a demethylase called KDM3B with the histone H3K9 mutant. “This suggests that these mutations inappropriately pull a demethylating enzyme onto chromatin, which then erases methylation marks in histones around it,” Morgan says.

Loss of methylation marks could allow expression of nearby genes. To confirm this, the group employed a Drosophila staining trick that allows experimenters to visualize how repressed genes are affected in entire tissues. The expression of KDM3B demethylase derepressed the gene expression in tissues such as salivary glands, just like the expression of the H3K9 mutant. This supports the idea that K-to-M mutations recruit a demethylase (like KDM3B) to demethylate chromatin on the K9 residue of H3.3 proteins in the neighborhood, where it likely uncoils chromatin to allow activation of genes that should be silenced.

This outcome could cause cancer in numerous ways. “One possibility might be that oncogenes that are usually silenced by methylation of residue 9 might be derepressed in the presence of the mutation,” says Hans-Martin Herz, Ph.D., a co-first author of the paper. But Herz is cautious in interpreting these findings, simply because, unlike the K27 mutations, mutations at residue K9 are not yet reported to be associated with cancer.

Intriguingly, other researchers recently reported a different K-to-M mutation (at residue 36 of histone H3.3) in chondroblastoma, a bone cancer sub-type. Why K-to-M mutations are so specific to a particular cancer is unknown, but Shilatifard says there can be little doubt that they play a central rather than a bystander role in tumorigenesis. “Uncharacterized K-to-M mutations may occur in other cancers,” he says. “Our work allows us to identify the molecular players involved in chromatin signaling in Drosophila and then apply those findings to human cells.”

source : http://www.sciencedaily.com/releases/2014/08/140829103216.htm