CWRU School of Medicine researchers discover new molecule linked to late-stage breast cancer

CLEVELAND -- Researchers at Case Western Reserve University School of Medicine have identified a molecule linked to more aggressive forms of breast cancer – a discovery that could point the way to potential cures.

Until this study, the ribonucleic acid (RNA) molecule called miR-181a had never before been tied to breast cancer metastasis. But when scientists found elevated levels of the molecule in late-stage breast cancer tissues, they in turn tested an inhibitor in mouse models. The approach not only prevented metastasis, but also extended the animals' lives.

"Overall, these findings reinforce our belief that the discovery of miR-181 will become a strong predictive biomarker for breast cancer metastasis, and that the high expression of miR-181 in tumor tissues will pave the way for the development of targeted therapies, better prognosis and increased patient survival," said lead researcher William Schiemann, PhD, associate professor of General Medical Sciences (oncology) at the medical school and a member of the Case Comprehensive Cancer Center.

The study appears online today in The Journal of Clinical Investigation (JCI) and will be published in the journal's January 2013 edition. Its authors include scientists at Case Western Reserve's School of Medicine, the Cleveland Clinic and University Hospitals.

"This work, published in the most important journal for patient-based discoveries, points us in the direction of a new genetic change in women with high-risk breast cancer," said Stanton Gerson, MD, director of the Case Comprehensive Cancer Center. "This research will impact the field by focusing us on new targets for treating and preventing metastasis in patients with breast cancer."

As breast-cancer tumors spread, they become less responsive to chemotherapy. Generating a cell-based system to replicate such changes enabled the research team to establish the molecule's effect on breast cancer metastasis. The team also linked high levels of miR-181 with decreased levels of a protein molecule called Bim, which kills cancer cells during chemotherapy. The combination of low Bim levels and elevated miR-181a levels allowed the breast cancers to -metastasize and resist chemotherapy.

"The identification of an RNA that regulates cell death may offer a natural molecule that can resensitize metastatic breast cancers to chemotherapy," Schiemann said.

Co-authors of the study, TGF-β Upregulates miR-181a Expression to Promote Breast Cancer Metastasis, are: Molly A. Taylor, of the Department of Pharmacology at the Case Western Reserve School of Medicine; Khalid Sossey-Alaoui, of the Lerner Research Institute of the Cleveland Clinic and the Case Comprehensive Cancer Center; Cheryl L. Thompson of the Department of Family Medicine at the Case Western Reserve School of Medicine and the Case Comprehensive Cancer Center; and David Danielpour of the Department of General –Medical Sciences (oncology) at the Case Western Reserve School of Medicine and the Case Comprehensive Cancer Center.

This grant was supported by the National Institutes of Health (NIH), the Komen Foundation and the University of Colorado Cancer Center Breast Program Gift Fund. Additional support was provided by pilot funds from the Case Comprehensive Cancer Center, which also provided expertise through the Athymic Animal and Xenograft Core, the Imaging Research Core, and the Tissue Resources Core. Finally, M.A. Taylor was supported by the Department of Defense (BC093128).

Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.

Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."

The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu

Case Comprehensive Cancer Center is an NCI-designated Comprehensive Cancer Center located at Case Western Reserve University. The center, now in its 25th year of funding, integrates the cancer research activities of the largest biomedical research and health care institutions in Ohio – Case Western Reserve, University Hospitals (UH) Case Medical Center, and the Cleveland Clinic. NCI-designated cancer centers are characterized by scientific excellence and the capability to integrate a diversity of research approaches to focus on the problem of cancer. It is led by Stanton Gerson, MD, Asa and Patricia Shiverick- Jane Shiverick (Tripp) Professor of Hematological Oncology, director of the National Center for Regenerative Medicine, Case Western Reserve, and director of the Seidman Cancer Center at UH Case Medical Center.