Abstract P1-07-02: Mesenchymal stem cell regulated microRNAs converge on the speech gene FOXP2 and regulate breast cancer metastasis

Abstract

Abstract About 90% of breast cancer mortalities are due to the spread of breast cancer cells (BCCs) from a primary tumor to distant organs, a process known as metastasis. However, the molecular mechanisms underlying metastasis remain poorly understood. Substantial evidence now supports a major role for the tumor microenvironment (TME) in catalyzing breast cancer metastasis. Indeed, observations indicate that proximal interactions between BCCs and cells of the TME induce altered gene expression programs in BCCs, allowing for the navigation of the various steps of the metastatic cascade. Our group and others observed that breast tumors recruit mesenchymal stem cells (MSCs): multipotent fibroblasts that normally exert tissue maintenance functions. We and others have observed that physical interactions of MSCs with BCCs are sufficient to drive their metastatic dissemination in murine xenograft models, via the induction of epithelial-mesenchymal transition (EMT) and dedifferentiation into stem cell-like states (cancer stem cells, or CSCs), states tightly associated with the capacity to seed new tumors (for example in foreign tissues) and with chemotherapeutic resistance. However, the TME-induced molecular pathways regulating such mechanisms remain poorly understood. MicroRNAs (miRNAs, miRs) are small noncoding RNAs that regulate gene expression via base-pair interactions with messenger RNAs (mRNAs), resulting in mRNA degradation or translational inhibition. Due to their ability to interact with large numbers of target mRNAs simultaneously, miRNAs are major regulators of cell identity, and thereby serve critical roles in metastasis. We performed miRnome-wide screening of MSC-stimulated BCCs to determine if TME interactions might contribute to BCC metastasis via the deregulation of miRNAs. We observed that proximal MSCs induce aberrant expression of a specific set of miRNAs in BCCs, which had not been previously implicated in breast cancer pathogenesis. These miRNAs, led by the transcriptionally co-regulated miR-199a-3p and miR-214, were sufficient to actuate the metastasis of weakly metastatic human BCCs in xenograft models. We observed that exogenous expression of the miRNAs provided BCCs with phenotypes and gene markers characteristic of CSCs, including enhanced tumor initiation capacities. Interestingly, we found that the MSC-induced miRNAs function as an interrelated network, and converge upon a common novel target: the speech associated gene FOXP2. Knockdown of FOXP2 phenocopied the metastatic phenotypes observed in MSC-induced miRNA expressing BCCs. Importantly, elevated levels of the MSC-induced miRNAs or depressed levels of FOXP2 could predict patient prognosis in the clinic. Altogether, our results incriminate FOXP2 and it’s MSC-induced miRNA regulatory network as novel determinants of breast cancer metastasis. Citation Format: Benjamin G Cuiffo, Antoine Campagne, George W Bell, Antonio Lembo, Francesca Orso, Evan Lien, Manoj K Bhasin, Monica Raimo, Summer E Hanson, Andriy Marusyk, Peiman Hematti, Kornelia Polyak, Odette Mariani, Stefano Volinia, Anne Vincent-Salomon, Daniela Taverna, Antoine E Karnoub. Mesenchymal stem cell regulated microRNAs converge on the speech gene FOXP2 and regulate breast cancer metastasis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-02.