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  • Consistent with our result Camacho Barquero and coworkers sh

    2022-05-19

    Consistent with our result, Camacho-Barquero and coworkers showed that curcumin reduced phospho-P38 MAPK. P-38 MAPK is a key effector of several downstream factors that eventually modulate the homing of monocytic cells during the onset of intestine inflammation (Camacho-Barquero et al., 2007). Along with our data, Lai and et al., demonstrated that curcumin decreased the phosphorylation of Akt and MAPK, the level of NF-κB and level of HER-2 in a dose-dependent manner in both BT-474 and SK-BR-3-h cells (Lai et al., 2012). While the protein level of phosphorylated FAK was increased in the current experiment, one explanation would be that the dose and time used in this study are different from the previous works.
    Conclusion
    Conflict of interest
    Acknowledgments This work derived from a Master of Science thesis in Lin28 1632 and supported by research grant from the Urmia University of Medical Sciences, Urmia, Iran. The authors thank the personnel of the Stem Cell Research Center (Tabriz University of Medical Sciences) and Cellular and Molecular Research Center, Urmia.
    Significance The EGFR and integrin/FAK signaling pathways are molecularly interconnected, resulting in redundancies and compensations that contribute to the aggressiveness and treatment resistance of TNBC. Here, we identified secreted protein Tinagl1 as an inhibitory factor for EGFR and integrin signaling. Biochemical characterization reveals that Tinagl1 inhibits EGFR and integrin/FAK through distinct mechanisms. Negative correlation between Tinagl1 level and activation status of EGFR and integrin/FAK was validated in patient samples. Moreover, Tinagl1 treatment, which mimics dual inhibition of EGFR and integrin/FAK signaling, overcomes the compensation commonly observed in single-modality treatments to suppress TNBC. Taken together, these data suggested that Tinagl1 may be developed as an effective therapeutic agent for TNBC by simultaneous targeting of both EGFR and integrin/FAK.
    Introduction As one of the most common malignant diseases among women, breast cancer also displays high degree of diversity in terms of pathological characteristics, disease progression, and response to treatments (Siegel et al., 2016, Sorlie et al., 2001). Triple-negative breast cancer (TNBC) is a heterogeneous subtype characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), and represents 12%–17% of all breast cancer cases (Foulkes et al., 2010). Patients having TNBC experience worse prognosis than those having any other subtypes owing to higher rates of recurrence and limited therapeutic options (Collignon et al., 2016). Moreover, TNBC is usually more aggressive and more likely to metastasize (Foulkes et al., 2010). Both innate and adaptive drug resistance is commonly observed in metastatic TNBC (Gonzalez-Angulo et al., 2007, Lehmann and Pietenpol, 2014). Therefore, effective targeted therapies for TNBC are urgently needed. Amplification or mutations of the epidermal growth factor receptor gene (EGFR) are associated with many types of cancer (Arteaga and Engelman, 2014). EGFR signaling is often highly active in TNBC (Costa et al., 2017), and is correlated with poor prognosis (Park et al., 2014). Although inhibitors against EGFR have been shown to suppress TNBC cell growth in vitro (Bao et al., 2017), these agents showed limited clinical effect in TNBC patients (Costa et al., 2017), possibly due to compensation by other oncogenic pathways in vivo (Rexer et al., 2009). Previous studies have demonstrated that EGFR signaling is extensively connected to integrin signaling in regulating many cellular functions, such as cell adhesion, migration, and oncogenic transformation (Desgrosellier and Cheresh, 2010). Overexpression and activation of integrin signaling has also been associated with the malignant features of breast cancer (Desgrosellier and Cheresh, 2010). One of the most prominent downstream effectors of integrin signaling is focal adhesion kinase (FAK), which has also been shown to drive breast cancer progression (Sulzmaier et al., 2014) and correlate with poor clinical outcome (Alexopoulou et al., 2014), particularly in TNBC patients (Golubovskaya et al., 2014). While these findings support the rationale of targeting the integrin/FAK signaling cascade in TNBC, clinical trials targeting integrin signaling again showed limited efficacy (Carter, 2010).