Trigger for Breast Cancer Spread Discovered

Researchers have identified elevated levels of interferon-stimulated gene 15 (ISG15), a ubiquitin like protein in a variety of cancers including breast cancer.

How the elevated ISG15 pathway contributes to tumorigenic phenotypes remains unclear.

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Shyamal Desai conducted the study with her co-investigators from the Louisiana State University School of Medicine in New Orleans, the University of Pennsylvania School of Medicine in Philadelphia, and the Robert Wood Johnson School of Medicine in New Jersey.

ISG15 also inhibits degradation of cellular proteins involved in cell motility, invasion, and metastasis, promoting breast cancer cell migration.

"Using ISG15 and UbcH8 gene knocked-down approach, our recent published and unpublished results explicitly demonstrated that the ISG15 pathway inhibits the ubiquitin-mediated proteasome-dependent protein degradation in breast cancer cells. We were the first to recognize this antagonizing effect of ISG15 in cancer cells," Desai said.

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However, others are increasingly coming to the same conclusion in their observations that ISG15 conjugation stabilizes cellular proteins.

"Given the crucial role of the ubiquitin or 26S proteasome pathway in normal cell homeostasis, one expects that ISG15-induced downregulation of the ubiquitin pathway must contribute to breast tumor cell viability. Concurrently, in this manuscript we demonstrate that ISG15 promotes breast cancer cell migration by inhibiting ubiquitin-mediated degradation of cellular proteins associated with cell motility, invasion and metastasis," Arthur Haas said.

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The researchers found that the elevated ISG15 pathway results in disruption of the cytoskeletal architecture effecting actin polymerization and formation of focal adhesions in breast cancer cells. Targeted knockdown of both ISG15 and UbcH8 resulted in reconstitution of the cytoskeletal architecture.

"Disruption of cellular architecture is a hallmark of cancer. The ISG15 pathway is also elevated in a variety of tumours. Our results therefore reveal that the ISG15 pathway which is aberrantly elevated in tumors could disrupt cell architecture and contribute to breast cancer cell motility," Desai said.

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"Because the cellular architecture is conserved and the ISG15 pathway is constitutively activated in tumour cells of different lineages, our observations in breast cancer must hold true for many other tumours.

"Strategies to decrease ISGylation could provide a therapeutic advantage for patients diagnosed with metastatic tumours overexpressing the ISG15 pathway," she added.

The study has been published in published in the January 2012 issue of Experimental Biology and Medicine.

Source-ANI