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Feature Article

'Micromanager' gene helps prevent breast cancer

New knowledge about the role of genes in health and disease promises to lead to safer, more effective treatments for an entire spectrum of diseases. VA research is at the forefront of genomic analysis efforts throughout the nation and the world.

As Joel Kupersmith, MD, VA's chief research and development officer has said, "The future of medicine is determined by research, and genomics is the direction for research in the 21st century."

Demonstrating the truth of Kupersmith's statement, two VA researchers at the Kansas City VA Medical Center's cancer research unit recently discovered a gene affecting the progression of breast cancer in women—one that might, in the future, result in new therapies for that deadly illness, and for pancreatic cancers, as well.

Sushanta K. Banerjee, PhD, and Snigdha Banerjee, PhD, detail their findings in their article "CCN5/WISP-2: A micromanager of breast cancer," published online in the Journal of Cell Communication and Signaling on April 10, 2012.i

"We discovered that CCN5/WISP-2, a member of the CCN family of growth factors, significantly suppresses the invasive characters of aggressive breast cancer cells," said Sushanta Banerjee.

A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation, and differentiation. The CCN family of growth factors is a group of proteins that help in the development of human organs, wound healing, the growth of new blood vessels (angiogenesis) and other biological phenomena.

In people with cancer, CCN proteins do not work properly. Within the past few years, different CCN proteins have been linked with either the progression of cancer cells or with their inhibition. The current paper demonstrates that the growth factor CCN5, which is found in the nucleus and cytoplasm of cells and in the body outside of cells, keeps cancer cells from transitioning into invasive cells. Invasive cells are cells that progress throughout the body.

"We demonstrated, for the first time, that CCN5 is differently expressed in breast tumor cell lines and human breast samples," said Sushanta Banerjee. The authors looked at two different types of breast cancer cells—those that had spread to other parts of the body, and those that had not.

They found that, in cancer cells that had spread to other organs, CCN5 was no longer being made—but in those cells that had remained localized within patients' breasts, CCN5 was still being created. As breast cancer progresses, the authors learned, cancer cells made less and less CCN5. Eventually, the level of CCN5 made by cancerous cells became undetectable.

Why does this linkage occur? According to the authors, CCN5 plays a role in cell plasticity—the ability of cells to take on the characteristics of cells elsewhere in the body. For example, scientists have determined that bone marrow stem cells transplanted elsewhere can change into lung or liver cells.

Nearly all cells share the same DNA (deoxyribonucleic acid), the hereditary material in humans and all other organisms. Therefore, something else has to tell the cells what they are supposed to do, such as grow hair, keep the heart beating, or keep infections from spreading. In recent years, scientists have come up with the concept of micromanagers to explain why similar cells accomplish different tasks.

CCN5, the authors believe, is a micromanager of cells in the breast—telling cells what their proper function in the body is and how that function should be accomplished. Its absence allows such cells to transform themselves—in this case, to malignant cancer cells.

The team's findings may lead to new treatments for both breast cancer and pancreatic cancer, a particularly virulent form of cancer to which CCN5 expression has also been linked.

"An inactivation of CCN5/WISP-2," they write, "�.contributes to the progression of breast and pancreatic cancers. (This) would predict that reactivation of CCN5, either alone or in combination with current therapeutic regimens, could provide a unique, alternative strategy for treating breast and pancreatic cancer."

As a next step, the Kansas City VA Medical Center's cancer research unit hopes to develop an animal model to test this hypothesis and to develop a new therapeutic approach to activate CCN5 in invasive breast cancer cells to block invasive growth and metastasis.

According to the article, breast cancer attacks one in every eight women, impacting nearly every family around the world. It is estimated that one in four cancers are breast cancer, and approximately 30 percent of women with breast cancer will develop the invasive form of the disease, which is ultimately incurable.

In addition to studies like this on cancer, VA's genomics research program is looking at the contribution of genes to amyotrophic lateral sclerosis (ALS); bipolar disorder and schizophrenia; posttraumatic stress disorder (PTSD), and other diseases and conditions.

VA Research's Million Veteran Program (MVP) is a trailblazing partnership with up to a million Veterans who are volunteering to help build one of the world's largest databases of genetic, military exposure, and health information, which will be applied to identify the connections between genes and health. For more information about MVP, visit www.research.va.gov/mvp.


i SK Banerjee, S Banerjee, "CCN5/WISP-2: A micromanager of breast cancer progression, J. Cell Commun. Signal, published online 10 April 2012, doi 10.1007/s12079-012-0158-2.


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