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Identification of a Tumor Suppressor Relay between the FOXP3 and the Hippo Pathways in Breast and Prostate Cancers

Departments of Surgery, Pathology, and Internal Medicine, Division of Immunotherapy, University of Michigan School of Medicine and Cancer Center, Ann Arbor, Michigan 48109, USA.
Cancer Research (Impact Factor: 9.28). 03/2011; 71(6):2162-71. DOI: 10.1158/0008-5472.CAN-10-3268
Source: PubMed

ABSTRACT Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in cancer of prostate, breast, liver, brain, and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer.

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Available from: Weiquan Li, Oct 30, 2014
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    • "Somatic mutations, deletions, and epigenetic inactivation of FoxP3 are reportedly widespread between human breast and prostate cancers (Liu et al, 2009; Zhang and Sun, 2010; Li et al, 2011), whereas no mutation was found in GC in this study. FoxP3 inhibits cell growth, cell proliferation, migration, and invasion in a lot of cancer cells (Liu et al, 2009; Zhang and Sun, 2010; Li et al, 2011), and inhibits breast and prostate cancer growth by transcriptionally repressing oncogenes HER2 (Zuo et al, 2007), c-Myc (Wang et al, 2009), Skp2 (Zuo et al, 2007), and increasing tumour suppressor gene p21 (Liu et al, 2009). Mice with heterozygous FoxP3 mutations succumbed to spontaneous mammary tumours (Zuo et al, 2007), whereas those with prostatespecific deletions of FoxP3 developed prostate intraepithelial neoplasia (Wang et al, 2009). "
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    ABSTRACT: Background: Forkhead Box P3 (FoxP3) is thought to be a key transcription factor in regulatory T cells (Tregs), and recent data indicate that it is expressed in several tumour cells. However, its precise roles in gastric cancer (GC) and the underlying mechanisms regulating the interaction between GC cells and lymphocytes remain unclear. Methods: FoxP3 expression was examined in tumour cells and Tregs in 150 cases of gastric precancer and cancer, and their prognostic significances were evaluated, respectively, using a tissue microarray containing 135 GC patient samples with a mean 102-month follow-up. FoxP3 involvement in the tumour cells–lymphocytes interaction and its gene function were further investigated. Results: strong cytoplasmic staining of FoxP3 was observed in GC cells. FoxP3 protein expression in tumour cells predicts a good prognosis, whereas high-density Treg predicts a poor prognosis. Moreover, FoxP3 expression in GC cells increased after coculture with peripheral blood mononuclear cells through coculture systems. Upregulation of FoxP3 inhibited tumour growth in tumour-bearing nude mice. Conclusions: High FoxP3 expression in tumour cells predicts better survival in GC, possibility in relation to interaction between tumour cells and lymphocytes in microenvironment. Interfering with FoxP3 expression may open a new therapeutic strategy against tumour progression.
    British Journal of Cancer 02/2014; 110(6). DOI:10.1038/bjc.2014.47 · 4.82 Impact Factor
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    • "Given the critical roles of Wnt/b-catenin in development, stem cell function, and oncogenesis, Wnt/b-catenin signaling is regulated by a variety of signaling pathways and molecules (MacDonald et al., 2009). LATS2 as tumor suppressor has been found to be mutated or downregulated in several human cancers (Takahashi et al., 2005; Lee et al., 2009; Li et al., 2011). However, the molecular mechanism by which LATS2 suppresses oncogenesis is not fully understood. "
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    ABSTRACT: Abnormal activation of Wnt/β-catenin-mediated transcription is associated with a variety of human cancers. Here, we report that LATS2 inhibits oncogenic Wnt/β-catenin-mediated transcription by disrupting the β-catenin/BCL9 interaction. LATS2 directly interacts with β-catenin and is present on Wnt target gene promoters. Mechanistically, LATS2 inhibits the interaction between BCL9 and β-catenin and subsequent recruitment of BCL9, independent of LATS2 kinase activity. LATS2 is downregulated and inversely correlated with the levels of Wnt target genes in human colorectal cancers. Moreover, nocodazole, an antimicrotubule drug, potently induces LATS2 to suppress tumor growth in vivo by targeting β-catenin/BCL9. Our results suggest that LATS2 is not only a key tumor suppressor in human cancer but may also be an important target for anticancer therapy.
    Cell Reports 12/2013; DOI:10.1016/j.celrep.2013.11.037 · 7.21 Impact Factor
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    • "As a repressor, FoxP3 diminishes transcription of oncogenes like Erbb2 (Her2/neu, human epidermal growth factor receptor 2), a transmembrane receptor kinase particularly regulating the growth of breast cancer cells [11], of the transcription factor c-Myc [15], Skp2 (S-phase kinase-associated protein 2), a part of the ubiquitin protein ligase complex [14], or SATB1 (special AT-rich sequence-binding protein-1), a chromatin organizer and transcription factor [17]. As an activator, FoxP3 induces tumor suppressor p21, an inhibitor of cyclin-dependent kinases [16] or Lats2, a negative regulator of the transcription co-activator YAP (Yes-associated protein) that is involved in the Hippo pathway regulating cell proliferation and apoptosis [29]. Thus, by several mechanisms FoxP3 can interplay with the cell cycle and apoptotic mechanisms, generally yielding anti-proliferative and pro-apoptotic effects. "
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    ABSTRACT: The forkhead transcription factor FoxP3 is critically involved in the development and function of regulatory T cells (Tregs) that populate tumors and are considered as powerful parts of their immune evasion. However, also tumor cells are reported to express FoxP3. Since gliomas are particularly immunosuppressive tumors, we investigated the occurrence and possible functions of FoxP3 in these malignant cells. By quantitative RT-PCR, immunohistochemistry and FACS analysis, we detected FoxP3 in glioma cells in situ and in vitro. After exposure of glioma cell lines to chemotherapeutics, expression of FoxP3 was significantly enhanced, and it was dislocated from more nuclear to perinuclear localization. Overexpression of FoxP3 in glioma cell lines considerably favored apoptotic damage of nuclei, DNA fragmentation, increased cleavage of the pro-apoptotic enzyme poly(ADP-ribose) polymerase (PARP) and basal activities of effector caspases-3/7. In FoxP3-transfected cells, apoptotic stimuli like Camptothecin, Temozolomide or tumor necrosis factor-α synergistically enhanced caspases-3/7-activities over controls. Taking together, FoxP3 occurs in glioma cells, is induced by chemotherapeutics, and its expression is correlated with increased apoptosis of glioma cells, especially when propagated by apoptotic stimuli. Thus, FoxP3 is a novel pro-apoptotic transcription factor in gliomas that is critically involved in the action of apoptotic agents.
    Experimental Cell Research 12/2012; DOI:10.1016/j.yexcr.2012.11.018 · 3.37 Impact Factor
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