Rrp1b, a New Candidate Susceptibility Gene for Breast Cancer Progression and Metastasis

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Abstract
A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM) genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis. Metastasis, which is defined as the spread of malignant tumor cells from their original site to other parts of the body, accounts for the vast majority of solid cancer-related mortality. Our laboratory has previously shown that host germline-encoded variation modifies primary tumor metastatic capacity. Here, we detail how germline-encoded Rrp1b variation likely modulates metastasis. In mice, constitutional Rrp1b variation correlates with ECM gene expression, which are genes commonly differentially regulated in metastasis prone tumors. Furthermore, we demonstrate that Rrp1b expression levels are modulated by germline variation in mice with differing metastatic propensities, and that variation of Rrp1b expression in a highly metastatic mouse mammary tumor cell line modifies progression. Differential RRP1B functionality also appears to play an important role in human breast cancer progression. Specifically, we demonstrate that a microarray gene expression signature indicative of differential RRP1B expression predicts breast cancer-specific survival. Furthermore, we show that germline-encoded RRP1B variation is associated with markers of outcome in two breast cancer populations. In summary, these data suggest that Rrp1b may be a germline-encoded metastasis modifier in both mice and humans, which leads to the possibility that knowledge of RRP1B functionality and variation in breast cancer might facilitate improved assessment of prognosis.