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MiRNA-21 linked to tumor suppressor loss, herceptin resistance
Date:4/19/2010

of Texas Graduate School of Biomedical Sciences at Houston (GSBS). "MiRNA regulation is disrupted in most diseases and in all cancers." Altered expression of miRNA also has been linked to the development of resistance to chemotherapy drugs such as cisplatin.

The researchers suspected that overexpression of miRNA-21 leads to reduced levels of PTEN and, in turn, to resistance to Herceptin. Herceptin is a targeted therapy used to treat metastatic breast cancer. Like other targeted cancer treatments, Herceptin homes in on a specific abnormal gene to slow or shut down cancer growth. The target gene in Herceptin treatment is ErbB-2-also known as HER2/neu or HER2.

"Herceptin is the most successful example of targeted cancer therapy," Yu noted. "But only about one-third of patients benefit from this therapy as a single agent." PTEN loss is a key reason.

MiRNA-21's role in Herceptin resistance

The hypothesis was tested in three HER2-overexpressing breast cancer cell lines. In a series of experiments, miRNA-21 and/or a control miRNA were introduced and expressed in the HER2-overexpressing cell lines. The cells were then treated with Herceptin. The researchers found that cells with higher levels of miRNA-21 had reduced PTEN expression and were significantly more resistant to the drug than were the control cells.

The researchers also determined that miRNA-21 reduces PTEN expression by inhibiting PTEN messenger RNA at a specific site in the PTEN transcript in breast cancer cells.

In another experiment, when the researchers downregulated miRNA-21 in high HER2-expressing cells, cellular PTEN levels rose, and the cells became more sensitive to Herceptin compared to control miRNA cells.

The researchers then sought to determine the clinical relevance of their findings by measuring levels of miRNA-21 in tumor samples from patients with HER2-positive breast cancer treated with Herceptin. They found a significant correlat
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Contact: Scott Merville
smerville@mdanderson.org
713-516-4855
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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