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  • Butyrolactone 3 Consistent with our gene profiling analyses


    Consistent with our gene-profiling analyses showing that genes involved in mutual compensation of EGFR or integrin/FAK were significantly downregulated by Tinagl1 overexpression, treatment with r-Tinagl1 inhibited the activation of EGFR and FAK in vitro, and phenocopied the combined inhibition of integrin/FAK and EGFR signaling in animal models. We further confirmed the negative correlation between Tinagl1 protein level and the activation of EGFR and integrin/FAK in TNBC tumor samples. Taken together, our study indicated Tinagl1 as both a good prognosis marker and potential therapeutic agent for TNBC patients. While there is a clear trend that Tinagl1 Butyrolactone 3 is also correlated with prognosis of patients having breast cancer of other subtypes, the correlation is not as strong as in TNBC and is not statistically significant. This could be due to the following two reasons. First, tumor progression of ER/PR+ and HER2+ subtypes is predominantly influenced by the ER and HER2 pathways, respectively, which are not the major targets of Tinagl1. Second, EGFR and ITGB1 are highly expressed in TNBC tumors (Changavi et al., 2015, Yin et al., 2016), and expression levels of EGFR and the integrin β1 subunit correlated with poor clinical outcome and progression in TNBC (Liu et al., 2012, Yin et al., 2016). This suggests that EGFR and integrins α5β1 and αvβ1 may play critical roles in promoting TNBC progression. As Tinagl1 targets EGFR and integrin/FAK pathways via interacting with EGFR and β1, α5, and αv subunits, all these facts may contribute to the observation that Tinagl1 has more significant clinical importance in TNBC patients. Nevertheless, we believe that the inhibitory effect of Tinagl1 in breast cancer progress is not limited to TNBC; instead, Tinagl1 may have a universal effect on the breast cancers that are driven by EGFR and integrin/FAK signaling. This notion was supported by our studies using Tinagl1-KO in the MMTV-PyMT model. It has been reported that early stages of PyMT-induced tumor mimic the luminal B subtype of human breast cancer, which is ER/PR+. The tumors lose ER/PR expression when they progress to late stages (Lin et al., 2003). Moreover, previous studies indicated that the EGFR and integrin/FAK pathways are critical for PyMT tumor progression (Foy et al., 2013, Guan, 2010, Lahlou et al., 2007). Our results demonstrated that Tinagl1-KO promoted PyMT tumor initiation at early stages, and enhanced tumor growth and lung metastasis at later stages. These results further support the notion that Tinagl1 does not selectively suppress TNBC only. Future studies should explore the potential therapeutic benefit of Tinagl1 in diverse cancer types driven by EGFR and integrin pathways.
    Acknowledgments We thank G. Ren, W. Li, L. Wan, H.A. Smith, Z. Li, W. Lu, and other lab members for technical support and helpful discussions, C. DeCoste and K. Rittenbach for assistance with flow cytometry, M. Alpern and V. Buynevich of the University Medical Center of Princeton at Plainsboro for assistance in blood sample analysis, and H. Matsumoto of Utsunomiya University for providing the Tinagl1 knockout mice. This research was supported by the Brewster Foundation, and grants from the US Department of Defense (BC123187) (to Y.K.) and postdoctoral fellowships from Susan G. Komen (PDF17332118) and NJCCR (DFHS15PPCO21) (to M.S.). This research was also supported by the Pre-clinical Imaging and Flow Cytometry Shared Resources of the Rutgers Cancer Institute of New Jersey (P30CA072720).
    Introduction Hepatocellular carcinoma (HCC) is the most common liver cancer and the second leading cause of cancer related death in the world [1,2]. The standard treatments for HCC include surgical resection, liver transplantation, local ablation therapy, transhepatic arterial chemotherapy and embolization [3,4]. Recent advances in HCC diagnosis and therapeutics have led to improved survival in patients with HCC, however, almost all of HCC patients eventually develop recurrence and metastasis, which are the underlying causes of poor long-term survival after clinical treatment in HCC [5]. Thus, a better understanding the potential molecular mechanisms during HCC metastasis provides an opportunity for preventing the initiation of metastasis in early HCC patients and developing therapeutic strategies in advanced HCC patients.