Features Partner Sites Information LinkXpress
Sign In
Advertise with Us
RANDOX LABORATORIES

Events

06 Jun 2016 - 09 Jun 2016
22 Jun 2016 - 24 Jun 2016
04 Jul 2016 - 06 Jul 2016

Molecular Switch Stops Aggressive Breast Cancer Metastasis

By BiotechDaily International staff writers
Posted on 28 Jan 2013
Print article
Scientists have found the molecular switch that allows aggressive triple-negative breast cancer cells to grow the amoeba-like protuberances they need to slither away from a primary tumor and spread throughout the body.

The study’s findings, published in Cancer Cell, suggest a novel approach for developing agents to treat cancer once it has metastasized. “Metastasis can be lethal, and our findings point to potential targeted treatments to stop the spread of this aggressive breast cancer,” stated the study’s senior investigator, Dr. Vivek Mittal, an associate professor of cell and developmental biology and director of the Lehman Brothers Lung Cancer Laboratory at Weill Cornell Medical College (New York, NY, USA).

If these agents can be developed, according to the researchers, they would feasibly be the first to specifically treat cancer metastasis, importantly in patients whose tumors have already metastasized. They would also be among the first designed to restore the function of a microRNA (miRNA), a small, noncoding RNA that controls gene expression, which is vital to cancer spread. While distinct miRNA signatures have been identified for many tumor types, including different breast tumors, their specific roles in later steps of cancer metastasis has been unclear, according to Dr. Mittal.

In the study, researchers set out to identify a miRNA that impacts metastasis without affecting primary tumor growth, as well as focus on its underlying molecular processes and therapeutic potential against metastatic breast cancer. They discovered that a miRNA known as miR-708 is inhibited in metastatic triple negative breast cancer. They found that miR-708 acts as a metastatic tumor inhibitor, and when its function is reestablished, the tumors do not metastasize or form deadly macrometastases.

Triple negative breast cancer has the worst outcome of all breast cancer subtypes because of its high recurrence rate and metastatic spread. This is why the research team chose to examine the role of miRNAs in the spread of triple negative breast cancer, which accounts for 15%–25% of all breast tumors. The cancer is deemed “triple negative” because its tumor cells do not display two hormone receptors (estrogen and progesterone) or HER2/neu growth factor, which each form the basis of current targeted breast cancer treatments.

Using genome wide miRNA sequencing, Dr. Mittal and his research team found in human samples of triple negative breast cancer that miR-708 was significantly downregulated with its normal expression curtailed. In both laboratory cells and in animal studies, the researchers identified that the normal role of miR-708 is to inhibit the protein neuronatin, which is located on the membrane of a cell’s endoplasmic reticulum, an organelle that stores calcium. Neuronatin helps control how much calcium leaves that organelle.

“It is calcium that provides legs to cancer cells to help them escape a tumor. So miR-708 acts as a suppressor of metastasis by keeping neuronatin in check,” Dr. Mittal said. “If miR-708 is itself suppressed, there is an increase in production of neuronatin proteins, which then allows more calcium to leave the endoplasmic reticulum and activate a cascade of genes that turn on migratory pathways leading to metastasis.”

Researchers revealed that delivering synthetic miR-708, carried by bubbles of fat, halted metastatic outgrowth of triple-negative breast cancer cells in the lung of mice. This makes miR-708 an exciting therapeutic against metastatic breast cancer. The researchers also discovered that polycomb repressor complex proteins are responsible for silencing miR-708. These proteins modify the way DNA is packaged in order to epigenetically silence genes.

Dr. Mittal added that these findings suggest that pharmacologic agents now being assessed in lymphoma cancer cells may also help to restore miR-708 in triple-negative breast cancer. These drugs are designed to inhibit histone-lysine N-methyltransferase EZH2, the member of the polycomb group that directly silences miR-708. “It is exciting that there are now drugs that can turn off the silencing of these critical genes. They could very well work for this aggressive breast cancer,” said Dr. Mittal. “Finding that there may be a way to shut down the spread of an aggressive breast cancer—which is the only way that triple negative breast cancer can be controlled and lives spared—is very promising.”

“These study results are terrific,” remarked coauthor Dr. Linda Vahdat, director of the Breast Cancer Research Program, chief of the Solid Tumor Service and professor of medicine at Weill Cornell Medical College and medical oncologist at the Iris Cantor Women’s Health Center at New York-Presbyterian Hospital/Weill Cornell Medical Center. “It not only offers us an avenue to treat metastatic triple negative breast cancer in the short-term, but also gives us the roadmap to prevent metastases in the long-run. We are anxious to get this into the clinic and are working as quickly as possible towards that end.”

Related Links:

Weill Cornell Medical College



Print article

Channels

Genomics/Proteomics

view channel
Image: Follicular helper T-cells (TFH cells, shown in blue) play a crucial role in the maturation of antibody-producing B-cells (shown in green). Activated B-cells give rise germinal centers (shown in red), where mature B-cells proliferate and produce highly specific antibodies against pathogens. Top left: normal germinal center in a mouse tonsil. All others: Germinal centers fail to form when the interaction between ICOS and TBK1 is interrupted (Photo courtesy of Dr. Kok-Fai Kong, La Jolla Institute for Allergy and Immunology).

Molecular Pathway Controlling High-affinity Antibody Production Identified

A molecular pathway has been identified that controls formation of follicular helper T-cells (TFH cells) germinal centers and production of high-affinity antibodies through interaction with the inducible... Read more

Drug Discovery

view channel

Experimental Small-Molecule Anticancer Drug Blocks RAS-binding Domains

The experimental small-molecule anticancer drug rigosertib was shown to block tumor growth by acting as an RAS-mimetic and interacting with the RAS binding domains of RAF kinases, resulting in their inability to bind to RAS, which inhibited the RAS-RAF-MEK pathway. Oncogenic activation of RAS genes due to point mutations... Read more

Biochemistry

view channel
Image: A space-filling model of the anticonvulsant drug carbamazepine (Photo courtesy of Wikimedia Commons).

Wastewater May Contaminate Crops with Potentially Dangerous Pharmaceuticals

Reclaimed wastewater used to irrigate crops is contaminated with pharmaceutical residues that can be detected in the urine of those who consumed such produce. Investigators at the Hebrew University... Read more

Lab Technologies

view channel

Huge Modifiable Biomedical Database to Be Available on the Wikidata Site

Genome researchers are exploiting the power of the open Internet community Wikipedia database to create a comprehensive resource for geneticists, molecular biologists, and other interested life scientists. While efficiency in generating scientific data improves almost daily, applying meaningful relationships between... Read more

Business

view channel

European Biotech Agreement to Promote Antigen-Drug Conjugation Technology

Two European biotech companies have joined forces to exploit and commercialize an innovative, site-specific ADC (antigen-drug conjugate) conjugation technology. ProBioGen (Berlin, Germany), a company specializing in the development and manufacture of complex glycoproteins and Eucodis Bioscience (Vienna, Austria), a... Read more
Copyright © 2000-2016 Globetech Media. All rights reserved.