Context-Specific Effects of TGF-β/SMAD3 in Cancer Are Modulated by the Epigenome

Vidaković, Ana Tufegdžić; Rueda, Oscar M.; Vervoort, Stephin J.; Batra, Ankita; Goldgraben, Mae A.; Uribe-Lewis, Santiago; Greenwood, Wendy; Coffer, Paul J.; Bruna, Alejandra; Caldas, Carlos

doi:10.1016/j.celrep.2015.11.040

Cited by 40 publications

(34 citation statements)

References 46 publications

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“…However, mutations in the TGF-β pathway are only part of the repertoire of loss of function. For instance, other mechanisms, such as epigenetic regulation of the TGF-β pathway, context-dependent responses and regulation of the TGF-β pathway generate cell, tissue, and cancer specificity can lead to mechanistic loss of function in human disease reflecting the knockout phenotype [41, 44, 45]. Moreover, while gene dosage is critically important in this family, as haploinsufficiency phenotypes result in aberrant gut, brain and liver hypoplasia as well as GI carcinoma, other mechanisms such as targeted protein proteolysis also play an important role in regulating protein levels [46].…”

Section: Tgf-β Signaling In Stem Cells and Cancer: Mouse Models And Hmentioning

confidence: 99%

TGF-β signaling in liver and gastrointestinal cancers

Katz

Likhter

Jogunoori³

et al. 2016

Cancer Letters

110

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Transforming Growth Factor-β (TGF- β) plays crucial and complex roles in liver and gastrointestinal cancers. These include a multitude of distinct functions, such as maintaining stem cell homeostasis, promoting fibrosis, immune modulating, as a tumor suppressor and paradoxically, as a tumor progressor. However, key mechanisms for the switches responsible for these distinct actions are poorly understood, and remain a challenge. The Cancer Genome Atlas (TCGA) analyses and genetically engineered mouse models now provide an integrated approach to dissect these multifaceted and context-dependent driving roles of the TGF-β pathway. In this review, we will discuss the molecular mechanisms of TGF-β signaling, focusing on colorectal, gastric, pancreatic, and liver cancers. Novel drugs targeting the TGF-β pathway have been developed over the last decade, and some have proven effective in clinical trials. A better understanding of the TGF-β pathway may improve our ability to target it, thus providing more tools to the armamentarium against these deadly cancers.

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Section: Tgf-β Signaling In Stem Cells and Cancer: Mouse Models And Hmentioning

confidence: 99%

TGF-β signaling in liver and gastrointestinal cancers

Katz

Likhter

Jogunoori³

et al. 2016

Cancer Letters

110

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“…The epigenomes of BTIC-promoting vs BTIC-suppressing breast cancer cells differentially determine the subset of target genes that can be bound and activated by TGFβ/SMAD3, adding another layer of complexity to context-dependent signaling by TGFβ ( Figure 7 ). 293 …”

Section: Transforming Growth Factor Betamentioning

confidence: 99%

The crossroads of breast cancer progression: insights into the modulation of major signaling pathways

Velloso¹,

Bianco²,

Farias³

et al. 2017

OTT

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Cancer is the disease with highest public health impact in developed countries. Particularly, breast cancer has the highest incidence in women worldwide and the fifth highest mortality in the globe, imposing a significant social and economic burden to society. The disease has a complex heterogeneous etiology, being associated with several risk factors that range from lifestyle to age and family history. Breast cancer is usually classified according to the site of tumor occurrence and gene expression profiling. Although mutations in a few key genes, such as BRCA1 and BRCA2, are associated with high breast cancer risk, the large majority of breast cancer cases are related to mutated genes of low penetrance, which are frequently altered in the whole population. Therefore, understanding the molecular basis of breast cancer, including the several deregulated genes and related pathways linked to this pathology, is essential to ensure advances in early tumor detection and prevention. In this review, we outline key cellular pathways whose deregulation has been associated with breast cancer, leading to alterations in cell proliferation, apoptosis, and the delicate hormonal balance of breast tissue cells. Therefore, here we describe some potential breast cancer-related nodes and signaling concepts linked to the disease, which can be positively translated into novel therapeutic approaches and predictive biomarkers.

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“…The phenotype of LBH knockout mice is relatively mild, with reduced breast epithelial progenitor cell proliferation [16]. LBH has been implicated in Wnt signaling [29] and possibly MAP kinase signaling [13, 30]. However, we did not observe these effects in RA FLS [10].…”

Section: Discussionmentioning

confidence: 75%

Regulation of the Cell Cycle and Inflammatory Arthritis by the Transcription Cofactor LBH Gene

Matsuda

Hammaker

Topolewski

et al. 2017

The Journal of Immunology

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Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development gene (LBH) as a key dysregulated gene in RA and other autoimmune diseases. While some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined. Our cell cycle analysis studies show that LBH deficiency in FLS leads to S phase arrest and failure to progress through the cell cycle. LBH-deficient FLS had increased DNA damage and reduced expression of the catalytic subunit of DNA polymerase α. Decreased DNA polymerase α was followed by checkpoint arrest due to phosphorylation of checkpoint kinase 1 (CHK1). Because DNA fragments can increase arthritis severity in pre-clinical models, we then explored the effect of LBH deficiency in the K/BxN serum transfer model. Lbh knockout exacerbated disease severity, which is associated with elevated levels of IL-1β and CHK1 phosphorylation. These studies indicate that LBH deficiency induces S phase arrest that, in turn, exacerbates inflammation. Because LBH gene variants are associated with type I diabetes mellitus, systemic lupus erythematosus, RA, and celiac disease, these results suggest a general mechanism that could contribute to immune-mediated diseases.

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Context-Specific Effects of TGF-β/SMAD3 in Cancer Are Modulated by the Epigenome

Cited by 40 publications

References 46 publications

TGF-β signaling in liver and gastrointestinal cancers

TGF-β signaling in liver and gastrointestinal cancers

The crossroads of breast cancer progression: insights into the modulation of major signaling pathways

Regulation of the Cell Cycle and Inflammatory Arthritis by the Transcription Cofactor LBH Gene

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