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• W2079150623 abstract "Approximately 20% of brain metastases originate from breast cancer, which is the most common invasive cancer of women worldwide. HER2 inhibitors have revolutionized the treatment of HER2 positive breast cancer patients, but have no or marginal activity against brain metastases yet - which is becoming increasingly problematic, since 40% of HER2 positive breast cancer patients will eventually develop this devastating complication of the disease. Therefore we aimed to understand which step of the brain metastatic cascade is actually affected by HER2 overexpression; which is crucial for successful growth to a macrometastasis; and which is most amenable to a prophylactic therapy. For this we used our novel animal model which allows to non-invasively follow single metastasizing cancer cells through a chronic cranial window over time, using in vivo multiphoton microscopy. Human MDA-MB-231 breast cancer brain-seeking subclones with high HER2 expression or with control vector have been injected into the circulation of female nude mice. As shown before for other cancer entities, only a very small proportion of cancer cells initially arrested in brain capillaries can successfully form brain metastases, which was similar for both groups (1.02% vs 1.67% - for HER2 overexpression and vector control, respectively). However, more of the injected HER2+ cells managed to initially arrest compared with HER2- cells (47.5 vs. 27.7 per 100,000 injected cells). Moreover, they extravasated earlier, and showed more early interaction with brain capillaries leading to intensive vascular remodeling, but no angiogenesis. We therefore focussed on factors of early breast cancer cell - blood vessel - interaction, and found integrins to be overexpressed in HER2+ cells. In ongoing experiments, we test an integrin αvβ3-5 inhibitor regarding its activity to prevent the early metastatic steps, and find that these steps are markedly inhibitied in treated animals. Our results provide a better understanding of the breast cancer brain metastatic cascade, and the role of HER2. Importantly, they suggest that inhibition of crucial early steps involving cancer cell - blood vessel interactions via integrin pathways can serve as a well tolerated long-term prophylactic treatment for HER2-positive breast cancer patients which are at risk to develop brain metastases. Citation Format: Yunxiang Liao, Matthias Osswald, Brunilde Gril, Patricia Steeg, Wolfgang Wick, Frank Winkler. The role of HER2 in the brain metastatic cascade in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 403. doi:10.1158/1538-7445.AM2013-403" @default.
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• W2079150623 date "2013-04-15" @default.
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• W2079150623 title "Abstract 403: The role of HER2 in the brain metastatic cascade in breast cancer." @default.
• W2079150623 doi "https://doi.org/10.1158/1538-7445.am2013-403" @default.
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