Abstract
Abstract Breast cancer causes approximately 40,000 deaths each year in the United States alone. Collective epithelial invasion is an important process in tumor progression, and it also occurs in the normal mammary gland (MG) through specialized structures called terminal end buds (TEBs) that proliferate and migrate to drive ductal outgrowth during MG development. P190-B RhoGAP is highly expressed in TEBs, suggesting it may regulate the invasive process of MG development. Indeed, tetracycline-inducible p190-B overexpression causes perturbations in TEB morphology, stromal composition, and MG branching morphogenesis. In the current study, we analyzed the gene expression patterns of MECs isolated from p190-B overexpressing mice to determine how p190-B regulates epithelial morphogenesis as well as stromal-epithelial interactions. We investigated the expression patterns of p190-B and investigated the effects of overexpression in MCF-7 breast cancer cells. We further investigated the effects of p190-B overexpression on primary MECs in a three-dimensional (3D) culture MEC morphogenesis assay in reconstituted basement membrane (rBM) and in adhesion assays. Microarray results demonstrated that a large number of genes involved in regulating mitotic cell division and the PI3K pathway of proliferation/survival signaling are altered in p190-B overexpressing primary MECs. Real-time PCR confirmed a number of genes are significantly up- or down-regulated in these pathways. Consistent with these findings, p190-B localizes to the mitotic spindle and kinetochores during metaphase of mitosis and to the midbody at cytokinesis. Furthermore, overexpression of p190-B caused abnormal centrosome formation, multipolar spindles, failed cytokinesis, and multinucleation in MCF-7 cells. In addition, primary MECs overexpressing p190-B demonstrated increased adhesion to laminin and type IV collagen, components of the basement membrane, and primary MECs overexpressing p190-B cultured in rBM showed increased disrupted acinar formation, loss of cell polarity, and invasion. P190-B overexpression alters cell polarity and mitosis and regulates adhesive and invasive properties in MECs. These phenotypes may be critical for TEB structure and function during MG branching morphogenesis. We propose that p190-B overexpression may contribute to tumorigenesis by disrupting mitosis and promoting invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 312.
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