Abstract B42: Dichotomus role of profilin in early vs. late steps of breast cancer metastasis

Abstract

Abstract Profilin1 (Pfn1), an essential control element for actin polymerization, plays indispensable role in migration and proliferation of normal cells. Seemingly contrary to these essential cellular functions of Pfn1, its expression is downregulated in breast cancer, the significance of which is unclear. In this study, expression profiling of Pfn1 in human breast cancer specimens of various histopathological stages correlate lower Pfn1 expression levels with propensity to metastasize. Xenograft studies uncover a unique dichotomous role of Pfn1 in early vs late steps of breast cancer metastasis. Specifically, loss of Pfn1 expression promotes dissemination of breast cancer cells from the primary mammary tumor but metastatic colonization of breast cancer cells is critically dependent on Pfn1's function. In the context of dissemination, breast cancer cells exhibit increased sustenance of PI3K signaling and acquire a hyper-invasive phenotype (marked by MMP9 upregulation, faster invasion through collagen matrix) involving a PI3K-PI(3,4)P2 signaling axis when Pfn1 expression is suppressed. In addition, Pfn1-deficient breast cancer cells display increased proficiency to cross through an endothelial cell barrier (an obligatory step for vascular dissemination) in a VEGF-dependent manner, respectively. Gene expression profiling combined with biochemical analyses of secreted proteins show that loss of Pfn1 impacts expression of several other pro-invasive and pro-metastatic genes. Finally, correlated with hyper-invasive phenotype of breast cancer cells caused by Pfn1 depletion, we found that mammary-specific deletion of Pfn1 gene expedites ductal outgrowth. In summary, contrasting the well-established pro-migratory role of Pfn1 in the physiological contexts, our findings set the first in vivo example of a context-specific effect of loss of Pfn1 in cell motility-dependent processes such as mammary gland morphogenesis and metastatic dissemination. Citation Format: Partha Roy. Dichotomus role of profilin in early vs. late steps of breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B42.