High cholesterol fuels growth, spread of breast cancer

Nov. 28, 2013 — A byproduct of cholesterol functions like the hormone estrogen to fuel the growth and spread of the most common types of breast cancers, researchers at the Duke Cancer Institute report.

The researchers also found that anti-cholesterol drugs such as statins appear to diminish the effect of this estrogen-like molecule.

Published in the Nov. 29, 2013, edition of the journal Science, the findings are early, using mouse models and tumor cells. But the research for the first time explains the link between high cholesterol and breast cancer, especially in post-menopausal women, and suggests that dietary changes or therapies to reduce cholesterol may also offer a simple, accessible way to reduce breast cancer risk.

"A lot of studies have shown a connection between obesity and breast cancer, and specifically that elevated cholesterol is associated with breast cancer risk, but no mechanism has been identified," said senior author Donald McDonnell, Ph.D., chair of the Department of Pharmacology and Cancer Biology at Duke. "What we have now found is a molecule -- not cholesterol itself, but an abundant metabolite of cholesterol -- called 27HC that mimics the hormone estrogen and can independently drive the growth of breast cancer."

The hormone estrogen feeds an estimated 75 percent of all breast cancers. In a key earlier finding from McDonnell's lab, researchers determined that 27-hydroxycholesterol -- or 27HC -- behaved similarly to estrogen in animals.

For their current work, the researchers set out to determine whether this estrogen activity was sufficient on its own to promote breast cancer growth and metastasis, and whether controlling it would have a converse effect.

Using mouse models that are highly predictive of what occurs in humans, McDonnell and colleagues demonstrated the direct involvement of 27HC in breast tumor growth, as well as the aggressiveness of the cancer to spread to other organs. They also noted that the activity of this cholesterol metabolite was inhibited when the animals were treated with antiestrogens or when supplementation of 27HC was stopped.

The studies were substantiated using human breast cancer tissue. An additional finding in the human tissue showed a direct correlation between the aggressiveness of the tumor and an abundance of the enzyme that makes the 27HC molecule. They also noted that 27HC could be made in other places in the body and transported to the tumor.

"The worse the tumors, the more they have of the enzyme," said lead author Erik Nelson, Ph.D., a post-doctoral associate at Duke. Nelson said gene expression studies revealed a potential association between 27HC exposure and the development of resistance to the antiestrogen tamoxifen. Their data also highlights how increased 27HC may reduce the effectiveness of aromatase inhibitors, which are among the most commonly used breast cancer therapeutics.

"This is a very significant finding," McDonnell said. "Human breast tumors, because they express this enzyme to make 27HC, are making an estrogen-like molecule that can promote the growth of the tumor. In essence, the tumors have developed a mechanism to use a different source of fuel."

McDonnell said the findings suggest there may be a simple way to reduce the risk of breast cancer by keeping cholesterol in check, either with statins or a healthy diet. Additionally, for women who have breast cancer and high cholesterol, taking statins may delay or prevent resistance to endocrine therapies such as tamoxifen or aromatase inhibitors.

The next steps for research include clinical studies to verify those potential outcomes, as well as studies to determine if 27HC plays a role in other cancers, McDonnell said.

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Methylation signaling controls cancer growth

Nov. 28, 2013 — A study led by researchers at Boston University School of Medicine (BUSM) demonstrates a new mechanism involving a signaling protein and its receptor that may block the formation of new blood vessels and cancer growth. The findings are published in the December issue of Science Signaling.

Angiogenesis creates new blood vessels in a process that can lead to the onset and progression of several diseases such as cancer and age-related macular degeneration.

Vascular endothelial growth factor (VEGF) is a signaling protein produced by damaged cells, which binds to one of its receptors VEGFR-2, located on the surface of blood vessel cells. Once VEGF is bound to its receptor, it is activated and sends a biochemical signal to the inside of the blood vessel cell to initiate angiogenesis. There are currently multiple Federal Drug Administration-approved medications that target this process. However these medications are limited by insufficient efficacy and the development of resistance.

The researchers demonstrated that a biochemical process called methylation, which can regulate gene expression, also affects VEGFR-2, and this can lead to angiogenesis. Using multiple methods, the researchers were able to interfere with the methylation process of VEGFR-2 and subsequently block angiogenesis and tumor growth.

"The study points to the methylation of VEGFR-2 as an exciting, yet unexplored drug target for cancer and ocular angiogenesis, ushering in a new paradigm in anti-angiogenesis therapy," said Nader Rahimi, PhD, associate professor of pathology, BUSM, who served as the study's senior investigator.

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The above story is based on materials provided by Boston University Medical Center, via EurekAlert!, a service of AAAS.

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Despite growth reports, Africa mired in poverty

Oct. 1, 2013 — Despite continued reports of economic growth in Africa, much of the continent remains wracked by poverty, with roughly one in five citizens saying they frequently lack food, clean water and medical care, according to the largest survey of African citizens.

This suggests the growth is not trickling down to the poorest citizens or that actual growth rates are inflated, said Carolyn Logan, assistant professor of political science at Michigan State University and deputy director of the survey, called the Afrobarometer.

"The survey results show there is a disconnect between reported growth and the persistence -- in both frequency and severity -- of poverty among ordinary citizens," Logan said. "It's evident that African governments need to focus as much attention on poverty reduction efforts as they are on growing their economies."

The fifth round of the Afrobarometer, which comes out every several years, was released today in Johannesburg. Thirty-four countries were surveyed -- up from 20 countries during the last round of surveys in 2008-9 -- making it the most comprehensive look at life in Africa since the Afrobarometer was started in 1999.

The release of today's findings on poverty and economic conditions is the first of seven release events in African cities up through Dec. 12. Future topics include democracy, corruption and Internet usage.

According to the current findings, 17 percent of Africans say they frequently go without food, 22 percent lack clean water on a regular basis, and 20 percent often go without medical care. About 50 percent do without these necessities at least occasionally. The problem is particularly striking in West Africa and East Africa, and less so in the northern and southern regions of the continent.

In addition, 53 percent of Africans rated their national economy negatively. And 38 percent said their national economy has gotten worse in the past year.

Moreover, Africans give their governments failing marks for economic management. Fifty-six percent say they are doing a bad job of managing the economy and even higher numbers rate them poorly for improving the living standards of the poor (69 percent), creating jobs (71 percent) and narrowing income gaps (76 percent).

The findings come despite the fact that Africa's gross domestic product grew by an average of 4.8 percent between 2002 and 2011, making Africa a new darling of portfolio investors and prompting The Economist magazine to tag Africa as "The Hopeful Continent."

The Afrobarometer is an independent, nonpartisan research project co-founded by Michael Bratton, University Distinguished Professor at MSU. Bratton currently serves as senior adviser on the project.

Core partners of the survey include the Center for Democratic Development in Ghana; the Institute for Justice and Reconciliation in South Africa; the Institute for Empirical Research in Political Economy in the Republic of Benin; and the Institute for Development Studies at the University of Nairobi in Kenya.

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Researchers identify switch that controls growth of most aggressive brain tumor cells

Sep. 20, 2013 — Researchers at UT Southwestern Medical Center have identified a cellular switch that potentially can be turned off and on to slow down, and eventually inhibit the growth of the most commonly diagnosed and aggressive malignant brain tumor.

Findings of their investigation show that the protein RIP1 acts as a mediator of brain tumor cell survival, either protecting or destroying cells. Researchers believe that the protein, found in most glioblastomas, can be targeted to develop a drug treatment for these highly malignant brain tumors. The study was published online Aug. 22 in Cell Reports.

"Our study identifies a new mechanism involving RIP1that regulates cell division and death in glioblastomas," said senior author Dr. Amyn Habib, associate professor of neurology and neurotherapeutics at UT Southwestern, and staff neurologist at VA North Texas Health Care System. "For individuals with glioblastomas, this finding identified a target for the development of a drug treatment option that currently does not exist."

In the study, researchers used animal models to examine the interactions of the cell receptor EGFRvIII and RIP1. Both are used to activate NFκB, a family of proteins that is important to the growth of cancerous tumor cells. When RIP1 is switched off in the experimental model, NFκB and the signaling that promotes tumor growth is also inhibited. Furthermore, the findings show that RIP1 can be activated to divert cancer cells into a death mode so that they self-destruct.

According to the American Cancer Society, about 30 percent of brain tumors are gliomas, a fast-growing, treatment-resistant type of tumor that includes glioblastomas, astrocytomas, oligodendrogliomas, and ependymomas. In many cases, survival is tied to novel clinical trial treatments and research that will lead to drug development.

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Some immune cells appear to aid cancer cell growth

AppId is over the quota
AppId is over the quota

The immune system is normally known for protecting the body from illness. But a subset of immune cells appear to be doing more harm than good. A new study from researchers at the University of Michigan Comprehensive Cancer Center found that these cells, called myeloid derived suppressor cells, provide a niche where the cancer stem cells survive.

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Among the research institutions NCI funds across the United States, it currently designates 68 as Cancer Centers. Largely based in research universities, these facilities are home to many of the NCI-supported scientists who conduct a wide range of intense, laboratory research into cancer’s origins and development. The Cancer Centers Program also focuses on trans-disciplinary research, including population science and clinical research. The centers’ research results are often at the forefront of studies in the cancer field.

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