Transforming Growth Factor-beta (TGF-beta)-Inducible Gene TMEPAI Converts TGF-beta from a Tumor Suppressor to a Tumor Promoter in Breast Cancer

Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Cancer Research (Impact Factor: 9.33). 08/2010; 70(15):6377-83. DOI: 10.1158/0008-5472.CAN-10-1180
Source: PubMed


TMEPAI is a transforming growth factor-beta (TGF-beta)-induced transmembrane protein that is overexpressed in several cancers. How TMEPAI expression relates to malignancy is unknown. Here, we report high expression of TMEPAI in estrogen receptor/progesterone receptor-negative and human epidermal growth factor receptor-2-negative breast cancer cell lines and primary breast cancers that was further increased by TGF-beta treatment. Basal and TGF-beta-induced expression of TMEPAI were inhibited by the TGF-beta receptor antagonist SB431542 and overexpression of Smad7 or a dominant-negative mutant of Alk-5. TMEPAI knockdown attenuated TGF-beta-induced growth and motility in breast cancer cells, suggesting a role for TMEPAI in growth promotion and invasiveness. Further, TMEPAI knockdown decreased breast tumor mass in a mouse xenograft model in a manner associated with increased expression of phosphatase and tensin homologue (PTEN) and diminished phosphorylation of Akt. Consistent with the effects through the phosphatidylinositol 3-kinase pathway, tumors with TMEPAI knockdown exhibited elevated levels of the cell cycle inhibitor p27kip1 and attenuated levels of DNA replication and expression of hypoxia-inducible fator 1alpha and vascular endothelial growth factor. Together, these results suggest that TMEPAI functions in breast cancer as a molecular switch that converts TGF-beta from a tumor suppressor to a tumor promoter.

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Available from: Pothana Saikumar, Jul 16, 2014
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    • "Two genes (TMEPAI and DKK1) were studied based on their role in metastasis in ovarian cancer. TMEPAI is a TGFβ-induced negative regulator [18] and is involved in TGFβ-induced metastasis in breast carcinoma cell lines [18] but has never been reported to be co-regulated by p53 and Smads. DKK1 is an inhibitor of Wnt signaling, which is often upregulated in metastatic ovarian cancer, and is associated with poor prognosis [19]. "
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    ABSTRACT: Ovarian cancer is the most lethal gynecological disease affecting women in the US. The Cancer Genome Atlas Network identified p53 mutations in 96% of high-grade serous ovarian carcinomas, demonstrating its critical role. Additionally, the Transforming Growth Factor Beta (TGFβ) pathway is dysfunctional in various malignancies, including ovarian cancer. This study investigated how expression of wild-type, mutant, or the absence of p53 alters ovarian cancer cell response to TGFβ signaling, as well as the response of the ovarian surface epithelium and the fallopian tube epithelium to TGFβ. Only ovarian cancer cells expressing wild-type p53 were growth inhibited by TGFβ, while ovarian cancer cells that were mutant or null p53 were not. TGFβ induced migration in p53 null SKOV3 cells, which was not observed in SKOV3 cells with stable expression of mutant p53 R273H. Knockdown of wild-type p53 in the OVCA 420 ovarian cancer cells enhanced cell migration in response to TGFβ. Increased protein expression of DKK1 and TMEPAI, two pro-invasive genes with enhanced expression in late stage metastatic ovarian cancer, was observed in p53 knockdown and null cells, while cells stably expressing mutant p53 demonstrated lower DKK1 and TMEPAI induction. Expression of mutant p53 or loss of p53 permit continued proliferation of ovarian cancer cell lines in the presence of TGFβ; however, cells expressing mutant p53 exhibit reduced migration and decreased protein levels of DKK1 and TMEPAI.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "TMEPAI enhanced TGF-β-induced growth, motility, and invasion in breast cancer cells but decreased breast tumor mass in a mouse xenograft model. This decrease was associated with increased expression of PTEN (phosphatase and tensin homologue), an inhibitor of the PI3K-Akt/PKB pathway [80]. In addition, TMEPAI can sequester Smad proteins to decrease TGF-β signaling as part of a negative feedback loop, which diminishes the TGF-β/Smad-induced growth-inhibitory effects [81]. "
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    ABSTRACT: Smad proteins are the key intermediates of transforming growth factor-beta (TGF-β) signaling during development and in tissue homeostasis. Pertubations in TGF-β/Smad signaling have been implicated in cancer and other diseases. In the cell nucleus, Smad complexes trigger cell type- and context-specific transcriptional programs, thereby transmitting and integrating signals from a variety of ligands of the TGF-β superfamily and other stimuli in the cell microenvironment. The actual transcriptional and biological outcome of Smad activation critically depends on the genomic integrity and the modification state of genome and chromatin of the cell. The cytoplasmic and nuclear Smads can also modulate the activity of other signal transducers and enzymes such as microRNA-processing factors. In the case of breast cancer, the role of Smads in epithelial plasticity, tumor-stroma interactions, invasion, and metastasis seems of particular importance.
    Preview · Article · Feb 2012 · Breast cancer research: BCR
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