New agent might control breast-cancer growth and spread

April 22, 2013
The drug AS1411 works by blocking the cell's production of regulatory molecules called microRNA, some types of which are associated with cancer. Specifically, the drug inhibits a protein called nucleolin that plays a critical role in the microRNA maturation process. Left: Steps in the microRNA maturation process. Right: How AS1411 interferes with microRNA maturation. Credit: The Ohio State University Comprehensive Cancer Center

A new study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) suggests that an unusual experimental drug can reduce breast-cancer aggressiveness, reverse resistance to the drug fulvestrant and perhaps improve the effectiveness of other breast-cancer drugs.

The findings of the laboratory and animal study, published in the Journal of Experimental Medicine, suggest a new strategy for treating breast cancer, the researchers say.

The drug, called AS1411, belongs to a class of agents called G-rich aptamers. The agent works by blocking the cell's production of molecules called microRNA, some types of which are associated with cancer. Specifically, the drug inhibits a protein called nucleolin that plays a critical role in the microRNA (See figure).

MicroRNA molecules help cells control the amount and kinds of proteins they make, and abnormal levels of certain microRNAs are a hallmark of many cancers.

"This study of the role of nucleolin in micro RNA regulation has clear clinical implications," says principal investigator Dr. Carlo M. Croce, director of Ohio State's program and a member of the OSUCCC – James Molecular Biology and Cancer Genetics program.

"It supports a novel treatment for breast cancer that reduces cancer aggressiveness and restores drug-sensitivity by inhibiting the processing of specific microRNAs that are highly expressed in cancers."

First author Flavia Pichiorri, assistant professor of hematology, notes that nucleolin is a promising for microRNA modulation in .

"To our knowledge, this is the first large study to show a clear association between nucleolin and specific microRNAs that are causally involved in cancer," she says. "We also believe it is the first study to show that targeting nucleolin with a G-rich can control breast-cancer metastasis in an animal model through microRNA regulation."

The study's key technical findings include:

  • Nucleolin is present at abnormally high levels in breast cancer cells.
  • AS1411 reduces nucleolin levels and inhibits the processing of certain cancer-associated microRNAs, including miR-21, miR-103, miR-221 and miR-222, whose overexpression in breast cancer is associated with drug resistance and aggressiveness.
  • AS1411 affects breast-cancer-cell motility and invasiveness by reducing the expression of several genes targeted by nucleolin-related microRNAs (e.g., PTEN);
  • Impairing nucleolin in fulvestrant-resistant cells restores sensitivity to the drug, suggesting that agents targeting nucleolin can improve the effectiveness of conventional anti-cancer agents.

Explore further: How early breast tumors become deadly: A small group of molecules might hold the answer

Related Stories

How early breast tumors become deadly: A small group of molecules might hold the answer

February 7, 2012
Researchers have discovered a restricted pattern of molecules that differentiate early-stage breast tumors from invasive, life-threatening cancer. They also found a similar molecular signature that correlated with the aggressiveness ...

Study reveals mechanism of lung-cancer drug resistance

January 19, 2012
New research published in Nature Medicine indicates that targeted drugs such as gefitinib might more effectively treat non-small cell lung cancer if they could be combined with agents that block certain microRNAs.

MicroRNA controls malignancy and resistance of breast cancer cells

May 4, 2012
Many breast cancer patients are treated with a drug called tamoxifen. The substance blocks the effect of estrogen and thus suppresses the growth signals of this hormone in cancer cells. When resistance to the drug develops, ...

MicroRNA molecule may serve as biomarker, target for brain metastases in breast cancer patients

February 5, 2013
Researchers have identified two molecules that could potentially serve as biomarkers in predicting brain metastases in patients with breast cancer, according to data published in Cancer Research, a publication of the American ...

miR loss may power maligant transformation in chronic leukemia

July 5, 2012
Loss of a particular microRNA in chronic lymphocytic leukemia shuts down normal cell metabolism and turns up alternative mechanisms that enable cancer cells to produce the energy and build the molecules they need to proliferate ...

Recommended for you

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.