Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Findings Point to Molecular 'Achilles Heel' for Half of Breast Cancer Tumors

17.01.2008
Researchers show why agents now being tested provide new treatment strategy

Researchers at Lombardi Comprehensive Cancer Center at Georgetown University Medical Center have shown why a protein known as cyclin D1 may be the Achilles heel for breast tumors that are estrogen receptor positive (ER+) − which is the most common type of breast cancer.

In the December 10th online edition of the journal Oncogene, investigators say the findings support testing an experimental class of drugs that aim to inhibit the cyclin D1 protein in women with ER+ breast cancers. These agents are currently being tested in this disease as well as in many other types of cancer, the researchers say, and the study provides additional molecular support for their use in breast cancer.

“Everyone knows that cyclin D1 is a huge player in breast cancer, but no one has shown what happens when cyclin D1 is absent at the same time that the estrogen receptor is being over-expressed on tumors. Now we know the answers, and we hope these insights help further our understanding and treatment of breast cancer,” said the study’s lead author, Maria Silvina Frech, Ph.D., who is currently a postdoctoral researcher at the National Cancer Institute but who worked on the study at Georgetown.

... more about:
»CDK »Comprehensive »ER+ »ERA »Lombardi »cyclin D1 »gland »mammary

“These findings give insight into how drugs that indirectly inhibit cyclin D1 function, either those in testing or ones to be developed, might help a significant number of women with breast cancer,” said Priscilla Furth, M.D., a professor at the Lombardi Comprehensive Cancer Center who is the study’s senior investigator.

Cyclin D1 belongs to a family of cyclin genes whose proteins regulate cyclin-dependent kinases (CDKs), which in turn control cell division. CDKs are the main facilitators of cell proliferation cycle. Over-production of the Cyclin D1 protein or amplification (extra copies) of the gene have been observed in a number of cancers, and this study continued a body of research in Furth’s lab that has examined the relationship between ER+ breast cancer and cyclin D1.

In 2005 Furth and Frech published a study that demonstrated that over expression of ERá (the main estrogen receptor subtype that mediates cell growth and is the major player in ER+ breast cancer) in mice resulted in the development of the earliest form of breast cancer, ductal carcinoma in situ (DCIS). They then found that cyclin D1 was over expressed in these lesions but not in the surrounding normal tissue. “Once the cancer process begins, cyclin D1 starts being over-expressed,” Frech said. “This was an exciting finding, but it was not clear what the precise role cyclin D1 plays in ER+ cancer.”

To find out what the protein was doing in these breast tumors, Frech, Furth, Kathleen Torre, B.S., from Georgetown and Gertraud W Robinson, Ph.D. from NIDDK, NIH, decided to take a genetics approach to the problem. They created an animal model that both over-expressed ERá and lacked cyclin D1.

They thought they would see a decreased incidence in DCIS in the animals, but what they actually found was that they completely lacked the mammary gland tissue that normally encases breast milk ducts. “This was very surprising. Most of the cells that usually make up the gland were absent, replaced by other structural tissue that shouldn’t be there,” she said.

t was also puzzling, Frech said, because puberty-induced mammary gland development in female mice that simply lack cyclin D1 is essentially normal. It made no sense to researchers that coupling over expression of ERá with the absence of cyclin D1 would have a complete lack of mammary glands. “This was striking, very unusual,” she said.

The solution was also very challenging, said Frech, whose three years of work on the project earned her a Ph.D. They eventually found that when cyclin D1 is deleted, levels of another major cyclin family member − cyclin E − are increased. And over-production of cyclin E, in the developing gland of these ERá over expressing mice led to DNA damage and cell death. The question that remains unanswered is whether this situation would hold true in advanced cancers treated with agents that inhibit cyclin D1 function, she said.

They also discovered that while cyclin D1 was not necessary for maintenance of normal breast cells, it was essential for the proliferation of abnormal mammary gland cells − and this differential use of cyclin D1 seems to be unique to early breast cancer. “That supports the idea that reducing cyclin D1 in breast cancer cells would not harm normal cells,” she said. There are experimental agents now being tested in clinical trials that shut down cyclin D1 function by targeting CDKs, Frech said. For example, flavopiridol is a potent CDK inhibitor currently undergoing clinical trials for a variety of tumors including breast cancer. Clinical activity is encouraging when used in combination with other molecular targeted agents, she said.

The study was supported by grants from the Department of Defense and the National Institutes of Health.

About Lombardi Comprehensive Cancer Center
The Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Lombardi is one of only 39 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to http://lombardi.georgetown.edu.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through our partnership with MedStar Health). Our mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO), home to 60 percent of the university’s sponsored research funding.

Becky Wexler | EurekAlert!
Further information:
http://www.georgetown.edu

Further reports about: CDK Comprehensive ER+ ERA Lombardi cyclin D1 gland mammary

More articles from Life Sciences:

nachricht One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie

nachricht The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Magnetic nano-imaging on a table top

20.04.2018 | Physics and Astronomy

Start of work for the world's largest electric truck

20.04.2018 | Interdisciplinary Research

Atoms may hum a tune from grand cosmic symphony

20.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>