The purpose of this study is to understand translational mechanisms underlying the cooperativity between FGF and WNT signaling in cancer progression. FGF and WNT signaling, crucial pathways in mammary stem cell self-renewal, are frequently deregulated in human cancer. We previously showed that acute activation of FGF signaling in the mammary gland of pubertal mice with WNT hyperactivation dramatically accelerates cancer progression. FGF-WNT-hyperactive tumor cells exhibit enhanced activation of translational machinery. Given the potential involvement of translational regulation in FGF-WNT induced tumorigenesis, we employed ribosome profiling to identify selectively translated and ribosome associated RNAs induced by acute FGF activation in vivo. Many genes associated with RNA processing and transport were translationally upregulated. Interestingly, the most translationally upregulated transcript was Malat1, originally thought to be a nuclear-restricted long noncoding RNA (lncRNA) that regulates transcription of cancer-associated genes. Along with Malat1, many lncRNAs were associated with ribosomes in FGF-WNT tumors. Malat1's association with polysomes upon acute FGF activation was confirmed by direct polysome analysis. We also demonstrated that Malat1 transcripts are transported to the cytoplasm during G2/M transition, implicating that Malat1 may be translated into small novel peptides or involved in translation regulation during this particular phase of cell cycle. Additionally, there is evidence that Malat1 is a direct downstream target of WNT signaling. Our findings indicate that FGF activation potentially increases the translation efficiency of WNT-target oncogenes including lncRNAs like Malat1, unraveling a novel mechanism of crosstalk between lncRNAs and translational regulation in cancer progression.

Citation Format: Tuan M. Nguyen, Elena B. Kabotyanski, Lucas C. Reineke, Qianxing Mo, Peng Zhang, Xiang Zhang, Yiwen Chen, Joel Neilson, Richard E. Lloyd, Jeffrey M. Rosen. FGF-WNT cooperativity and the role of lncRNAs in translational regulation in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A03.