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Angiogenic Acceleration of Neu Induced Mammary Tumor Progression and Metastasis

¹Oncodevelopmental Biology Program, The Burnham Institute, La Jolla, California; ²The Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada; ³Molecular Oncology Group, Departments of Medicine and Biochemistry, McGill University, Montreal, Quebec, Canada; and ⁴Pathology Department, University of California, Davis, California

The Neu (ErbB2, HER2) member of the epidermal growth factor receptor family is implicated in many human breast cancers. We have tested the importance of increased angiogenic signaling in the NeuYD [mouse mammary tumor virus (MMTV)-Neu^ndl-YD5] mammary tumor model. Transgenic mice expressing vascular endothelial growth factor (VEGF)₁₆₄ from the MMTV promoter were generated. These mice expressed VEGF₁₆₄ RNA and protein at 20- to 40-fold higher levels throughout mammary gland development but exhibited normal mammary gland development and function. However, in combination with the NeuYD oncogene, VEGF₁₆₄ expression resulted in increased vascularization of hyperplastic mammary epithelium and dramatic acceleration of tumor appearance from 111 to 51 days. Gene expression profiling also indicated that the VEGF-accelerated tumors were substantially more vascularized and less hypoxic. The preferential vascularization of early hyperplastic portions of mammary epithelia in NeuYD;MMTV-VEGF animals was associated with NeuYD RNA expression, disorganization of the tight junctions, and overlapping transgenic VEGF expression. NeuYD;MMTV-VEGF₁₆₄ bigenic, tumor-bearing animals resulted in an average of 10 tumor cell colonies/lung lodged within vascular spaces. No similar lung colonies were found in control NeuYD mice with similar tumor burdens. Overall, these results demonstrate the angiogenic restriction of early hyperplastic mammary lesions. They also reinforce in vivo the importance of activated Neu in causing disorganization of mammary luminal epithelial cell junctions and provide support for an invasion-independent mechanism of metastasis.

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