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    Correction: The pleiotropic effects of TNF? in breast cancer subtypes is regulated by TNFAIP3/A20 (Oncogene, (2019), 38, 4, (469-482), 10.1038/s41388-018-0472-0)
    (Nature Publishing Group, 2019) Lee, Eunmi; Ouzounova, Maria D.; Piranlıoğlu, Raziye; Ma, Minh Thu; Güzel, Mustafa; Marasco, Daniela; Chadli, Ahmed; Gestwicki, Jason E.; Cowell, John K.; Wicha, Max S.; Hassan, Khaled A.; Korkaya, Hasan
    Following publication of this article the authors noted that the Acknowledgments section had been omitted. This section should read as follows.
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    Dual activity of minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment
    (2024) Köksalar Alkan, Fulya; Çağlayan, Ahmet Burak; Alkan, Hilmi Kaan; Gündüz, Yunus Emre; Şensoy, Özge; Öztürk, Gürkan; Korkaya, Hasan
    Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.
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    Dual function of HSP70 in cytoprotection of tumor cells and generation of immunosuppressive tumor microenvironment
    (American Association for Cancer Research, 2021) Korkaya, Hasan; Köksalar Alkan, Fulya; Ece Arslan, Z.; Altıntaş, Esra; Piranlıoğlu, Raziye; Lee, Eunmi; Wicha, Max S.
    [Abstract Not Available]
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    Short-term diet restriction but not alternate day fasting prevents cisplatin-induced nephrotoxicity in mice
    (MDPI AG, 2020) Günebakan, Evrin; Yalçın, Esra; Çikler Dülger, Esra; Yiğitbaşı, Ahmet; Ateş, Nilay; Çağlayan, Aysun; Beker, Mustafa Çağlar; Şahin, Kâzim; Korkaya, Hasan; Kılıç, Ertuğrul
    Cisplatin (CP) is one of the most preferred platinum-containing antineoplastic drugs. However, even in nontoxic plasma concentrations, it may cause kidney injury. To be able to increase its effective pharmacological dose, its side effects need to be regarded. Diet restriction (DR) has been demonstrated to improve cellular survival in a number of disorders. In this context, we investigated the role of DR in CP-induced nephrotoxicity (CPN). Besides alternate DR, animals were exposed to DR for 3 days prior or after CP treatment. Here, we observed that both 3 days of DR reverses the nephrotoxic effect of CP, which was associated with improved physiological outcomes, such as serum creatine, blood-urea nitrogen and urea. These treatments significantly increased phosphorylation of survival kinases PI3K/Akt and ERK-1/2 and decreased the level of stress kinase JNK were noted. In addition, the activation level of signal transduction mediator p38 MAPK phosphorylation was higher particularly in both three-day DR groups. Next, animals were fed with carbohydrate-, protein- or fat-enriched diets in the presence of CP. Results indicated that not only fasting but also dietary content itself may play a determinant role in the severity of CPN. Our data suggest that DR is a promising approach to reduce CPN by regulating metabolism and cell signaling pathways.
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    The pleiotropic effects of TNF alpha in breast cancer subtypes is regulated by TNFAIP3/A20 (vol 38, pg 469, 2018)
    (Nature Publishing Group, 2019) Lee, Eunmi; Ouzounova, Maria; Piranlıoğlu, Raziye; Ma, Minh Thu; Güzel, Mustafa; Marasco, Daniela; Chadli, Ahmed; Gestwicki, Jason E.; Cowell, John Kenneth; Wicha, Max S.; Hassan, Khaled A.; Korkaya, Hasan
    Following publication of this article the authors noted that the Acknowledgments section had been omitted. This section should read as follows.
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    The pleiotropic effects of TNF? in breast cancer subtypes is regulated by TNFAIP3/A20
    (Nature Publishing Group, 2019) Lee, Eunmi; Ouzounova, Maria; Piranlıoğlu, Raziye; Ma, Minh Thu; Güzel, Mustafa; Marasco, Daniela; Chadli, Ahmed; Gestwicki, Jason E.; Cowell, John Kenneth; Wicha, Max S.; Hassan, Khaled A.; Korkaya, Hasan
    TNF alpha is a pleiotropic cytokine which fuels tumor cell growth, invasion, and metastasis in some malignancies, while in others it induces cytotoxic cell death. However, the molecular mechanism by which TNF alpha exerts its diverse effects on breast cancer subtypes remains elusive. Using in vitro assays and mouse xenografts, we show here that TNF alpha contributes to the aggressive properties of triple negative breast cancer (TNBC) cell lines via upregulation of TNFAIP3(A20). In a striking contrast, TNF alpha induces a potent cytotoxic cell death in luminal (ER+) breast cancer cell lines which fail to upregulate A20 expression. Overexpression of A20 not only protects luminal breast cancer cell lines from TNF alpha-induced cell death via inducing HSP70-mediated anti-apoptotic pathway but also promotes a robust EMT/CSC phenotype by activating the pStat3-mediated inflammatory signaling. Furthermore, A20 overexpression in luminal breast cancer cells induces aggressive metastatic properties in mouse xenografts via generating a permissive inflammatory microenvironment constituted by granulocytic-MDSCs. Collectively, our results reveal a mechanism by which A20 mediates pleiotropic effects of TNF alpha playing role in aggressive behaviors of TNBC subtype while its deficiency results in TNF alpha-induced apoptotic cell death in luminal breast cancer subtype.