Abstract
Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-β induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-β-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3′ UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-β signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.
Highlights
Metastasis to bone is the most frequent cause of breast cancer morbidity and mortality
We chose to screen for miRNAs that were downregulated in the MDA-MB-231(SA) cells and the miRNAs that were predicted to target IL11 according to the miRanda, PicTar, or TargetScan prediction algorithm
MiR-210, whose high expression has previously been associated with increased likelihood of distant metastasis [22] and poor clinical outcome [23] in breast cancer, was 6.5-fold downregulated in the MDA-MB-231(SA) cells
Summary
Metastasis to bone is the most frequent cause of breast cancer morbidity and mortality. Available therapies are able to alleviate painful symptoms but bone metastatic cancer remains incurable. This is due to limited understanding of the integral molecular and cellular determinants of the bone metastatic process. Gene expression profiling of clinical tumor samples and experimental in vivo studies have revealed sets of genes whose expression in tumor cells correlates with their metastatic potential [1] Many of these genes have been shown to play an important role in different phases of metastatic progression, but a therapeutically applicable common regulatory mechanism governing a multitude of these gene expression changes in tumor cells is yet to be discovered. The specific role of miRNAs in the bone metastatic process of breast cancer has not been extensively studied, but available early results suggest miRNAs as potential key regulators [4,5,6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
