ASCO--microRNA responsible for herceptin resistance(can overcome it)

[Lani]

AACR: MicroRNA Linked to Trastuzumab Resistance

By Ed Susman, Contributing Writer, MedPage Today
Published: April 20, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Study discusses preclinical, laboratory experiments indicating that microRNA, when overexpressed in tumor cells, appears to interfere with the ability of trastuzumab (Herceptin) to control breast cancer cell proliferation.


Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
WASHINGTON -- Researchers here said that microRNA, when overexpressed in tumor cells, appears to interfere with the ability of trastuzumab (Herceptin) to control breast cancer cell proliferation in vitro.
Investigators at the University of Texas M.D. Anderson Cancer Center, Houston, said the specific microRNA-21 appears to block the phosphatase and tensin homolog (PTEN) gene.

"PTEN acts as a tumor suppressor and is involved in regulating cell proliferation and death," said Sumaiyah K. Rehman, a graduate research assistant in the center's Department of Molecular and Cellular Oncology, who presented the findings at the annual meeting of the American Association for Cancer Research. "When it is expressed normally, cells proliferate more slowly or stop growing."

"We know that there are signaling pathways in cancer cells that drive malignancy and progression," senior author Dihua Yu, MD, PhD, deputy chair of the department, added in a press release. "PTEN acts as a brake on those monogenic signaling pathways, and PTEN loss has been found in about 40 percent of breast cancers. So it is well-documented that PTEN loss is correlated with a poor clinical outcome in breast cancer patients."

MicroRNAs influence gene expression by targeting specific messenger RNAs which, in turn, ensure that proteins and their products are produced correctly. Interference from microRNAs can disrupt or alter this normal protein production. Rehman noted that microRNA regulation "is disrupted in most diseases and in all cancers."

In laboratory experiments, Rehman demonstrated that overexpression of microRNA-21 in breast cancer cells leads to reduced levels of PTEN and, in turn, to resistance to Herceptin. But by introducing an antisense molecule targeted at microRNA-21, investigators restored or maintained the functioning of trastuzumab, she told MedPage Today.

In three HER2-overexpressing breast cancer cell lines, researchers introduced microRNA-21 and/or a control microRNA. The cells were then treated with trastuzumab. 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 then sought to determine the clinical relevance of their findings by measuring levels of microRNA-21 in tumor samples from 37 patients with HER2-positive breast cancer treated with trastuzumab.

In the seven patients with high levels of microRNA-21, six had progressive disease. Among the 30 patients whose tumors had low or intermediate levels of microRNA-21, 22 achieved an objective response in tumor shrinkage or stable disease while eight patients had progressive disease (P=0.007).

Rehman and Yu had no relevant disclosures.


Primary source: American Association for Cancer Research
Source reference:
Rehman S, et al, "MiR-21 upregulation in breast cancer cells leads to PTEN loss and Herceptin resistance" AACR 2010; Abstract 4033.