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  • We then explored the potential

    2019-11-04

    We then explored the potential roles of vigilin, along with other proteins which have affinity for the 69 nt CSF-1R element, in breast cancer cells. The sequestration of these proteins by excess 69 nt pyrimidine-rich element increases CSF-1R levels (Figures 2 and 4), and as a result, increases the degree of adhesion, motility, and invasion of breast cancer polymyxin sulfate (Figure 4). It is notable that the degree of effect on up-regulation of CSF-1R is similar whether the terminal 578 nt CSF-1R mRNA 3′UTR containing the pyrimidine-rich sequence is overexpressed (Figure 4), or just the 69 nt pyrimidine-rich sequence (Figure 2). This underlies the impact of this small pyrimidine-rich region on post-transcriptional regulation of CSF-1R mRNA, as well as on breast cancer cellular behavior in vitro. We have previously shown that vigilin overexpression can inhibit breast cancer cell invasiveness and motility in vitro [9]. Here, we show that deletion of the 69 nt vigilin binding element obviates effect of competition with excess CSF-1R mRNA 3′UTR on enhancement of in vitro parameters of breast cancer cellular behavior. Thus vigilin, along with other yet unidentified 69 nt binding proteins, via its binding of the CSF-1R mRNA 3′UTR pyrimidine-rich element, may have a role in the inhibition of tumor behaviors such as breast cancer invasion and metastasis. Neutralizing CSF-1R antibody inhibits the invasiveness of the excess CSF-1R mRNA 3′UTR containing breast cancer cells, suggesting the actions of the pyrimidine-rich sequence are at least in part due to the up-regulation of CSF-1R protein in these cells. Finally, we are the first to report vigilin expression in human breast tissues and in particular in relation to transition to DCIS. CSF-1R has been well associated with metastatic spread and poor survival of breast cancer [8]. IHC analysis indicates that vigilin expression appears to be lower in transition to DCIS than in normal human breast tissues (Figure 5).
    Conclusions CSF-1R is an important mediator of breast cancer development, metastasis, and survival. The 69 nt CSF-1R RNA binding element in its 3′UTR suppresses translation of CSF-1R. This pyrimidine-rich, non-AU-rich, 3′UTR element has been characterized to date to bind both vigilin and HuR. Vigilin, a nucleo-cytoplasmic binding protein, down-regulates mRNA stability as well as translation of target mRNAs. The full length 69 nt element is required for stable vigilin binding. This 69 nt element also mediates in vitro phenotypes of adhesion, motility, and invasion of breast cancer cells. We are the first to show that vigilin is strongly expressed in normal human breast tissue, with its expression decreasing in the transition to ductal carcinoma in situ.
    Acknowledgments We appreciate Steven J. Gibson and Arpan Ajit Patel for their excellent technical support. We also appreciate Women\'s Cancers, as well as Ray Nagle, MD, PhD, for support of this project. This work was supported by DOD grant DAMD 17-02-1-0633 (to SKC), Arizona Biomedical Research Commission grant #0802 (to SKC), and the Rodel Foundation (to SKC). Research reported in this publication was also supported by the National Cancer Institute Cancer Center Support Grant P30 CA023074 and used the Tissue Acquisition and Cellular /Molecular Analysis Shared Resource (TACMASR) for providing the breast slides.
    Introduction Immunotherapy has shown tremendous promise in cancer treatment.1, 2 Therapeutic antibodies targeting programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) have resulted in major breakthroughs in cancer treatment.3, 4 Nevertheless, the durable responses induced by PD-1 or PD-L1 blockade alone are limited in patients with colorectal cancer,5, 6 and the poor therapeutic effects have been linked to tumor-intrinsic or -extrinsic mechanisms for escaping immune surveillance.7, 8, 9, 10 Recent preclinical studies have polymyxin sulfate indicated that combination strategies would be an ideal approach to overcome immunosuppression, thus improving the therapeutic efficacy.