Critical complex mechanisms involved in the metastasis of deadly triple-negative breast cancers (TNBC) have been identified. These tumors are extremely difficult to treat, frequently return after remission, and are the most aggressive form of breast cancer in women. The discovery of this critical interaction of mechanisms could be used to develop new life-saving treatments to kill metastatic tumors in TNBC.

“In previous findings published over the past 10 years, our teams have described key mechanisms in these critical proteins,” said Khalid Sossey-Alaoui, PhD, of the Lerner Research Institute of the Cleveland Clinic in Ohio. “A key component in the deadly metastatic potential of TNBC tumors is that they spread through tissues outside the breast very quickly. The two proteins that we studied, WAVE3 and TGF-β, when together, promote tumor aggressiveness.”

“We found important biological implications,” said William Schiemann, PhD, of Case Western Reserve School of Medicine and Case Comprehensive Cancer Center, also in Cleveland, Ohio. “For the first time, we uncovered an interplay between the two proteins that can inhibit or suppress TNBC—a discovery that has the potential to inhibit proliferations of the tumor.”

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The next step in the research process is to find a way to deliver inhibitors to the tumor. Using nanoparticles, the Sossey-Alaoui/Schiemann team hopes to deliver therapies directly to the site of the tumor and reverse the disease. Their goal is to move this basic research into clinical trials in the next 3 years. The current study was published in Breast Cancer Research and Treatment (2013;142[2]:341-355).

Metastasis is a complex, multistage process in which primary tumor cells invade the surrounding cells, tissues, and organs; integrate into blood vessels; and survive and move throughout the body. Metastasis of primary mammary tumors accounts for the vast majority of deaths in breast cancer patients. The 5-year survival rate for patients with breast cancer drops precipitously from 98% for patients with localized disease to 23% for those with metastatic disease.

This study found that the transforming growth factor-β (TGF- β) induces the expression of WAVE3 in metastatic breast cancer cells. WAVE3 is an actin-binding protein with roles in cell morphology, actin polymerization, cytoskeleton remodeling, cell motility, and invasion. When expression of WAVE3 was depleted, TGF-β could not initiate the epithelial-mesenchymal transition that cells undergo in the process of metastasis. This research suggests that inactivating WAVE3 may stop the metastasis that TGF-β stimulates.