Sequential Activation of NFAT and c-Myc Transcription Factors Mediates the TGF-β Switch from a Suppressor to a Promoter of Cancer Cell Proliferation

Singh, Garima; Singh, Shiv K.; König, Alexander; Reutlinger, K; Nye, Monica D.; Adhikary, Tillman; Eilers, Martin; Gress, Thomas M.; Fernández-Zapico, Martín E.; Ellenrieder, Volker

doi:10.1074/jbc.m110.100438

Cited by 85 publications

(81 citation statements)

References 40 publications

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“…Whereas TGFβ treatment may lead to the activation of calcineurin and consequently of NFAT proteins, [29][30][31] in some model systems, treatment with CsA leads to the production of TGFβ. [32][33][34] TGFβ exposure induces an arrest in cell cycle progression of primary endothelial cells while it promotes growth of transformed cells.…”

Section: Resultsmentioning

confidence: 99%

Cyclosporin A inhibits colon cancer cell growth independently of the calcineurin pathway

et al. 2012

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Section: Resultsmentioning

confidence: 99%

Cyclosporin A inhibits colon cancer cell growth independently of the calcineurin pathway

et al. 2012

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“…Multiple signaling pathways have been shown to promote EMT in various cancers (Kalluri 2009). Despite having both tumor growth promoting and inhibiting roles of TGF-β-signaling in breast carcinogenesis (Singh et al 2010;Novitskiy et al 2011), many studies found TGF-β-signaling can induce EMT under specific microenvironments (Sato et al 2010;Takahashi et al 2010). TGF-β-signaling-induced EMT is Smad 3/4 dependent, which eliminates the p53 tumor suppressor function by activating the E3 ubiquitin ligase (Araki et al 2010) which degrades this protein.…”

Section: Ccn5 Is a Negative Regulator Of Micro-rna 10bmentioning

confidence: 99%

CCN5/WISP-2: A micromanager of breast cancer progression

Banerjee

2012

J. Cell Commun. Signal.

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The gain of plasticity by a subset of cancer cells is a unique but common sequence of cancer progression from epithelial phenotype to mesenchymal phenotype (EMT) that is followed by migration, invasion and metastasis to a distant organ, and drug resistance. Despite multiple studies, it is still unclear how cancer cells regulate plasticity. Recent studies from our laboratory and others' proposed that CCN5/WISP-2, which is found intracellularly (in the nucleus and cytoplasm) and extracellularly, plays a negative regulator of plasticity. It prevents the EMT process in breast cancer cells as well as pancreatic cancer cells. Multiple genetic insults, including the gain of p53 mutations that accumulate over the time, may perturb CCN5 expression in non-invasive breast cancer cells, which ultimately helps cells to gain invasive phenotypes. Moreover, emerging evidence indicates that several oncogenic lesions such as miR10b upregulation and activation of TGF-β-signaling can accumulate during CCN5 crisis in breast cancer cells. Collectively, these studies indicate that loss of CCN5 activity may promote breast cancer progression; application of CCN5 protein may represent a novel therapeutic intervention in breast cancer and possibly pancreatic cancer. Keywords Breast cancer . Cell signaling . Invasion and apoptosis Human breast cancer: an overviewBreast cancer, a genetically heterogeneous disease (Lichy et al. 2000;Polyak 2011), is the most commonly identified malignant disease in Western women after nonmelanocytic skin cancer. It attacks one in eight women (~12%), impacting nearly every family worldwide. It is estimated that more than 1 in 4 cancers are breast cancer. Approximately 30% of these women will develop the invasive form of the disease, which is ultimately incurable. Therefore, it is a major health issue for women. Incidence of breast cancer generally increases with age. Women approaching or at menopause have an increased risk of breast cancer. In addition to age, several other factors (i.e., personal and environmental) are associated with the development of this disease. Fortunately, the breast cancer related death rate has been reduced recently due, in part, to early diagnosis and decreased intake of carcinogenic hormones or other unknown factors. However, our current therapeutic options for advanced stages of breast cancer are still fairly limited and ineffective. Thus, there is a need to better understand the molecular basis of the genesis of breast cancer and its progression in order to design targeted, molecularly based therapies.Like other cancers, the genesis of ductal carcinoma in the breast is the result of unprogrammed genetic and epigenetic changes, which lead to mal-regulation of cellular growth.

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“…46 Transforming growth factor beta (TGFB) has also been known to interact with PP2A, which might contribute to the contradictory regulation of p-AKT and MYC. [47][48][49] In metastatic breast cancer (MDA-MB-231), the transition of tumour-suppressive role to tumour-promoting role of TGFB has been attributed to the nuclear factor of activated T-cells (NFAT), which is shown to drive epithelial-to-mesenchymal transition (EMT) and c-MYC expression. 50 Here, we suggest another potential mechanism for this transition.…”

Section: Discussionmentioning

confidence: 99%

CIP2A expression predicts recurrences of tamoxifen-treated breast cancer

et al. 2017

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CIP2A is emerging as an oncoprotein overexpressed commonly across many tumours and generally correlated with higher tumour grade and therapeutic resistance. CIP2A drives an oncogenic potential through inhibiting protein phosphatase 2A, stabilizing MYC, and promoting epithelial-to-mesenchymal transition, although further biological mechanisms for CIP2A are yet to be defined. CIP2A protein expression was studied by immunohistochemistry in oestrogen receptor-positive primary breast cancers (n = 250) obtained from the Leeds Tissue Bank. In total, 51 cases presented with a relapse or metastasis during adjuvant treatment with tamoxifen and were regarded as tamoxifen resistant. CIP2A expression was scored separately for cytoplasmic, nuclear, or membranous staining, and scores were tested for statistically significant relationships with clinicopathological features. Membranous CIP2A was preferentially expressed in cases who experienced a recurrence during tamoxifen treatment thus predicting a worse overall survival (log rank = 8.357, p = 0.004) and disease-free survival (log rank = 21.766, p < 0.001). Cox multivariate analysis indicates that it is an independent prognostic indicator for overall survival (hazard ratio = 4.310, p = 0.013) and disease-free survival (hazard ratio = 5.449, p = 0.002). In this study, we propose the assessment of membranous CIP2A expression as a potential novel prognostic and predictive indicator for tamoxifen resistance and recurrence within oestrogen receptor-positive breast cancer.

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Sequential Activation of NFAT and c-Myc Transcription Factors Mediates the TGF-β Switch from a Suppressor to a Promoter of Cancer Cell Proliferation

Cited by 85 publications

References 40 publications

Cyclosporin A inhibits colon cancer cell growth independently of the calcineurin pathway

Cyclosporin A inhibits colon cancer cell growth independently of the calcineurin pathway

CCN5/WISP-2: A micromanager of breast cancer progression

CIP2A expression predicts recurrences of tamoxifen-treated breast cancer

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