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Last Updated: Oct 11, 2012 - 10:22:56 PM
Research Article
Breast Cancer Channel

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Latest Research : Cancer : Breast Cancer

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Why tumour cells are herceptin resistant

Mar 8, 2008 - 7:47:45 AM , Reviewed by: Dr. Sanjukta Acharya
"Herceptin revolutionized the treatment of breast cancer," said Colleen Sweeney, associate professor of biochemistry and molecular medicine. "But our clinical experiences indicate that there is room for improvement. We wanted to find out what was reducing Herceptin's effectiveness in some cases."

[RxPG] UC Davis Cancer Center researchers have discovered a likely reason why some tumor cells are inherently resistant — or become resistant over time — to the popular breast cancer drug trastuzumab, commonly referred to by the brand name Herceptin. One in four women with breast cancer are candidates for treatment with Herceptin, which decreases the risk of relapse and prolongs patient survival. For 30 to 50 percent of patients, however, the drug does not work.

"Herceptin revolutionized the treatment of breast cancer," said Colleen Sweeney, associate professor of biochemistry and molecular medicine, co-director of the UC Davis Cancer Center Breast Cancer Research Program and senior author of the study, which is published in the March 1 issue of Cancer Research. "But our clinical experiences indicate that there is room for improvement. We wanted to find out what was reducing Herceptin's effectiveness in some cases."

Introduced in 1998, Herceptin has been used to treat women whose tumor cells test positive for multiple copies of the HER2 gene. Every normal cell carries HER2, which helps cells grow, divide and repair themselves. During cancer development, however, this gene creates extra copies of itself, which helps cancer cells grow and spread. In combination with other medications, Herceptin slows this process by blocking the HER2 cell-growth signal.

Previous research by the UC Davis team showed that another gene called MET could be activated at the same time as HER2, making tumor cells more invasive as a result. For the current study, Sweeney decided to find out if MET also contributes to Herceptin resistance. To do this, the researchers conducted a series of experiments involving three HER2-positive cell lines and 10 HER2-positive primary breast tumors.

They found MET expressed at moderate levels in three HER2 tumor specimens and at high to very high levels in four others. Using one of the cell lines, they showed that MET and HER2 activation together substantially increased tumor-cell proliferation. They went on to show that inhibiting or depleting MET in two HER2 overexpressing cell lines makes HER2-positive breast cancer cells more susceptible to the drug Herceptin, while activating MET reduces the drug's effectiveness. Additional analyses of publicly available microarray data from studies conducted at Yale University showed that MET is overexpressed in Herceptin-resistant tumors.

"The MET gene is waiting in the wings and can take over for HER2 when it is targeted with Herceptin," Sweeney explained. "Some HER2-positive tumor cells express MET and these cells respond to Herceptin by making even more copies of MET. When a woman gets breast cancer, we currently test her tumor for HER2 but don't take MET into account. We believe that looking at just HER2 status is no longer going to tell us the whole story."

Because the proteins encoded by HER2 and MET are both known as receptor tyrosine kinases, or RTKs, Sweeney predicted that breast cancer research will increasingly rely on proteomic as well as genetic testing of tumors that goes beyond HER2 and focuses on finding therapies that target MET and other RTKs expressed in HER2-positive breast cancers. The search is now on for affordable, high-throughput technology that makes possible the complete evaluation of the expression profiles of kinomes, which are families of related RTKs.

"Access to this type of technology will allow us to more rapidly find novel drugs to block the activity of kinomes or even individual kinases and greatly improve the efficacy of existing treatments," she said.

For the next phase of her research, Sweeney will utilize a larger number of patient specimens and attempt to determine whether MET expression predicts Herceptin resistance.

"We need to confirm that the MET receptor is going to be a viable target. If we again find a significant correlation between MET and Herceptin resistance, the next step will be drug studies targeting MET in an animal model," she said.

Publication: March 1 issue of Cancer Research

Funding information and declaration of competing interests: The study was funded by the National Institutes of Health and the U.S. Department of Defense Breast Cancer Research Program. It was made possible with tissues and cell lines obtained from the American Type Culture Collection and the National Cancer Institute Cooperative Human Tissue Network as well as with data obtained from Affymetrix Gene Array

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 About Dr. Sanjukta Acharya
This news story has been reviewed by Dr. Sanjukta Acharya before its publication on RxPG News website. Dr. Sanjukta Acharya, MBBS is the chief editor for RxPG News website. She oversees all the medical news submissions and manages the medicine section of the website. She has a special interest in diabetes and endocrinology.
RxPG News is committed to promotion and implementation of Evidence Based Medical Journalism in all channels of mass media including internet.
 Additional information about the news article
UC Davis Cancer Center is a National Cancer Institute-designated cancer center that cares for 9,000 adults and children with cancer each year from throughout the Central Valley and inland Northern California. The center's Breast Cancer Program provides comprehensive, multidisciplinary services for patients with all stages of breast cancer. Patients receive all of their care in one location, from a team of top academic physicians with expertise in hematology and oncology, surgical oncology, radiation oncology, pathology, plastic and reconstructive surgery, and diagnostic radiology/mammography. These experts work together to develop individualized treatment plans for each patient
For any corrections of factual information, to contact the editors or to send any medical news or health news press releases, use feedback form

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