MicroRNA Linked to Breast Cancer Metastasis and Decreased Patient Survival

Cancer researchers have identified a molecule that enhances the metastatic potential of breast cancers by promoting epithelial-mesenchymal transition, migratory and invasive phenotypes, and by stimulating resistance to anoikis.

Anoikis is a form of programmed cell death that is induced by anchorage-dependent cells detaching from the surrounding extracellular matrix (ECM). Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide essential signals for growth or survival. When cells are detached from the ECM, there is a loss of normal cell-matrix interactions, and they may undergo anoikis. However, metastatic tumor cells may escape from anoikis and invade other organs.

Investigators at Case Western Reserve University (Cleveland, OH, USA) attempted to recapitulate tumor and metastatic microenvironments by using biomechanically compliant or rigid 3-dimensional culture systems and combining them with global microRNA (miRNA) profiling analyses to identify miRNAs that were upregulated in metastatic breast cancer cells by TGF-beta (transforming growth factor-beta receptor 2). TGF-beta acts as an antiproliferative factor in normal epithelial cells and at early stages of cancer development. When a cell is transformed into a cancer cell, parts of the TGF-beta signaling pathway are mutated, and TGF-beta no longer controls the cell. These cancer cells and surrounding stromal cells (fibroblasts) begin to proliferate. Both types of cell increase their production of TGF-beta. This TGF-beta acts on the surrounding stromal cells, immune cells, endothelial and smooth muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive.

The investigators reported in the December 17, 2012, online edition of the Journal of Clinical Investigation that expression of a specific miRNA, miR-181a, was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in human breast cancer patients.

Mechanistically, inactivation of miR-181a elevated the expression of the pro-apoptotic molecule Bim, which sensitized metastatic cells to anoikis. MiR-181a expression was essential in driving metastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice.

“Overall, these findings reinforce our belief that the discovery of miR-181a will become a strong predictive biomarker for breast cancer metastasis, and that the high expression of miR-181a in tumor tissues will pave the way for the development of targeted therapies, better prognosis, and increased patient survival,” said senior author Dr. William Schiemann, associate professor of general medical sciences at Case Western Reserve University. “The identification of an RNA that regulates cell death may offer a natural molecule that can resensitize metastatic breast cancers to chemotherapy.”

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