Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewThe “good-cop bad-cop” TGF-beta role in breast cancer modulated by non-coding RNAs
Introduction
We have come a long way from the first known reference to cancer pathologies, which dates back to approximately 3000 BCE Written by Ancient Egyptians, the reference indicates a lack of treatment [1]. For almost five thousand years, the field of oncology has accumulated a tremendous amount of information at both macroscopic and molecular levels, but no cure is still available for many cancers. Numerous key pathways have been described in an attempt to develop targeted strategies for the treatment of specific subtypes of malignancy. The traditional clinical tools are now replaced by molecular diagnosis, prognosis and treatment approaches based on differential and specific coding and non-coding gene signatures. Non-coding RNAs (ncRNAs) are currently in the center of scientific interest due to their wide range of implications in numerous malignant scenarios through regulation of gene expression.
Epithelial to mesenchymal transition (EMT), a well-known physiological route has emerged as a key process involved in cancer due to the invasiveness and motility characteristics it gives to cells. Loss of the epithelial phenotype in favor of the mesenchymal one endows tumor cells with increased motility, allowing them to migrate and invade different sites and thus encouraging cancer progression and metastasis [2]. This type of transition can be activated by a number of conditions such as hypoxia, immunosuppression and a list of extracellular growth factor mediators e.g. TGF-beta (transforming growth factor-beta), EGF (epithelial growth factor), TNF-alpha (tumor necrosis factor – alpha), IGF (insulin growth factor), FGF (fibroblast growth factor) and PDGF (platelet derived growth factor) [3]. The action of this diverse palette of stimuli is transduced under the form of SNAI1, TWIST, SLUG, ZEB1/2 and Aurora A regulation. These transcription factors are capable of epithelial marker suppression and induction of the mesenchymal phenotype [4]. Previous research activities have demonstrated the regulatory role of ncRNAs, that can act as oncogenes or tumor suppressors in malignant pathologies [5], [6]. The complementarity between ncRNAs and specific coding genes transforms these sequences from “junk DNA” (as they were previously thought to be) into important regulators of different pathologies, especially cancer [5]. Out of all the ncRNAs, microRNAs (miRNAs) and long.
non-coding RNAs (lncRNAs) are the most studied ones, with new sequences constantly discovered [7]. Each ncRNA has specific actions according to the pathology in question. Among them, miRNAs, sequences of 19–25 nucleotides are able to target multiple genes, standing as important regulators of extensive signaling networks [8], [9]. EMT is also partially controlled by ncRNAs, particular miRNAs, which are described as being actively involved in the reprogramming process and have been proposed as therapeutic targets in the attempt to minimize cancer development [10].
The purpose of this review consists in the comprehensive presentation of the updated TGFβ-induced EMT along with the oncogenic or suppressor action of ncRNAs in breast cancer, namely microRNAs and lncRNAs.
Section snippets
TGFβ – “good cop bad cop” switch
The TGFβ family members (with name coming from the main representative TGFβ) are cytokines synthesized by white blood cell lineages and consist of over 40 proteins with different functions including activins, growth/differentiation factors, inhibins and bone morphogenetic proteins [11], [12]. Among them the most studied protein from this group is TGFβ that has three isomeric forms (TGFβ-1, -2, -3). As in the case of other cytokines, the general role of these immunomodulating agents is
Relationship between EMT-TGFβ signaling pathways
EMT represents a signaling pathway that has an ubiquitous functional distribution, being classified into three different types according to the specific roles within the organism. The initial studies surrounding the EMT process associated this pathway with normal development during embryogenesis, heart-valve shaping [56], cell lineage in neural crest development [57] and palatal fusion [58]; all these implications being listed in the Type 1 category or development category [59]. Further studies
Conclusion and further perspectives
The hallmarks of EMT are becoming increasingly associated with aggressive forms of breast cancer and low survival rates among patients. Considering that this phenotypical switch can trigger drug resistance, invasion and metastasis (all of which are currently critical points in clinical scenarios), inhibition of EMT could represent an important milestone in mammary cancer treatment. In this regard, several strategies have been tested using preclinical models.
TGFβ is involved in multiple
Declaration of interest
The authors have nothing to disclose.
Transparency Document
Acknowledgements
The authors wish to thank to Sereen Fatima (British native speaker and a student at the Faculty of Medical and Human Sciences at the University of Manchester) for her helpful contribution regarding grammar and spelling corrections.
This work was supported in part by Project PN-II-RU-TE-2014-4-1464; 307 from 01/10/2015 - Targeting the TGFβ pathway: an alternative for breast cancer therapy; POSCCE 709 Breast Impact and Project HO-18/2014, funded by Medical University of Plovdiv.
References (158)
- et al.
Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic
Biochim. Biophys. Acta
(2009) - et al.
Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis
Dev. Cell
(2008) - et al.
microRNAs as oncogenes and tumor suppressors
Dev. Biol.
(2007) The epithelial-mesenchymal transition (EMT) phenomenon
Ann. Oncol.
(2010)- et al.
Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition
Curr. Opin. Cell Biol.
(2009) - et al.
Transforming growth factor beta (TGF-beta) and inflammation in cancer
Cytokine Growth Factor Rev.
(2010) - et al.
Coordinate transcriptional and translational repression of p53 by TGF-beta1 impairs the stress response
Mol. Cell
(2013) - et al.
Targeting the TGFbeta pathway for cancer therapy
Pharmacol. Ther.
(2015) - et al.
MicroRNAs and cancer—new paradigms in molecular oncology
Curr. Opin. Cell Biol.
(2009) - et al.
Crosstalk between TGF-beta signaling and the microRNA machinery
Trends Pharmacol. Sci.
(2012)
miR-125b functions as a key mediator for snail-induced stem cell propagation and chemoresistance
J. Biol. Chem.
Transforming growth factor-beta and the hallmarks of cancer
Cell. Signal.
Induction of epithelial-mesenchymal transition by transforming growth factor beta
Semin. Cancer Biol.
Coupled reversible and irreversible bistable switches underlying TGFbeta-induced epithelial to mesenchymal transition
Biophys. J.
Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions
J. Biol. Chem.
MiR-200, a new star miRNA in human cancer
Cancer Lett.
miR-200c inhibits melanoma progression and drug resistance through down-regulation of BMI-1
Am. J. Pathol.
Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells
Cell
The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2
J. Biol. Chem.
The miR200 family of microRNAs regulates WAVE3-dependent cancer cell invasion
J. Biol. Chem.
History of cancer, ancient and modern treatment methods
J. Cancer Sci. Ther.
The regulatory role of MicroRNAs in EMT and cancer
J. Oncol.
MicroRNAs in cancer
Annu. Rev. Med.
The non-coding RNA journal club: highlights on recent papers—3. Non-coding
RNA
Molecular pathways: microRNAs, cancer cells, and microenvironment
Clin. Cancer Res.
MicroRNAs and cancer therapy - from bystanders to major players
Curr. Med. Chem.
Dissimilar effects of LY 294002 and PD 098059 in IGF-I-mediated inhibition of TGF-beta1 expression and apoptosis in bovine mammary epithelial cells
J. Physiol. Pharmacol.
Transforming growth factor beta1 (TGFbeta1) in physiology and pathology
Endokrynol. Pol.
Transforming growth factor-beta and the immune response: implications for anticancer therapy
Clin. Cancer Res.
Transforming growth factor-beta and the immune response to malignant disease
Clin. Cancer Res.
Biology of transforming growth factor-beta signaling
Curr. Pharm. Biotechnol.
TGF-beta biology in mammary development and breast cancer
Cold Spring Harb. Perspect. Biol.
Noncanonical TGF-beta signaling during mammary tumorigenesis
J. Mammary Gland Biol. Neoplasia
The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells
J. Mammary Gland Biol. Neoplasia
Regulation of endothelial cell plasticity by TGF-beta
Cell Tissue Res.
Targeted inactivation of beta1 integrin induces beta3 integrin switching, which drives breast cancer metastasis by TGF-beta
Mol. Biol. Cell
Duel nature of TGF-beta signaling: tumor suppressor vs. tumor promoter
Curr. Opin. Oncol.
Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways
J. Cell Biol.
TGF-beta-induced nuclear localization of Smad2 and Smad3 in Smad4 null cancer cell lines
Oncogene
The roles of TGF-beta signaling in carcinogenesis and breast cancer metastasis
Breast Cancer
Two faces of TGF-beta1 in breast cancer
Mediat. Inflamm.
Epithelial-mesenchymal transition and drug resistance in breast cancer (review)
Int. J. Oncol.
Cell adhesion system and human cancer morphogenesis
Cancer Sci.
Resveratrol sensitizes tamoxifen in antiestrogen-resistant breast cancer cells with epithelial-mesenchymal transition features
Int. J. Mol. Sci.
Transforming growth factor beta engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab
Mol. Cell. Biol.
Doxorubicin in combination with a small TGFbeta inhibitor: a potential novel therapy for metastatic breast cancer in mouse models
PLoS One
Targeting the TGFbeta signalling pathway in disease
Nat. Rev. Drug Discov.
Small molecule inhibition of transforming growth factor beta signaling enables the endogenous regenerative potential of the mammalian Calvarium
Tissue Eng. A
The use of cystatin C to inhibit epithelial-mesenchymal transition and morphological transformation stimulated by transforming growth factor-beta
Breast Cancer Res.
Dasatinib: a novel therapy for breast cancer?
Expert Opin. Investig. Drugs
Cited by (40)
The ncRNA-TGF-β axis: Unveiling new frontiers in colorectal cancer research
2024, Pathology Research and PracticeTransforming growth factor-β signaling: From tissue fibrosis to therapeutic opportunities
2023, Chemico-Biological InteractionsCitation Excerpt :MiRNAs also regulate TGF-β signal transduction [32]. Several miRNAs are TGF-β signal transducers, targeting ligands, receptors, R-Smad, Co-Smad, I-Smad, and non-Smad pathway components as well as downstream targets of TGF-β signal transduction [33–36]. A number of miRNAs, such as let-7b and miR 29, have been shown to inhibit TGF-β1 signaling and slow the progression of renal fibrosis.
Altered expression of miR-181 affects cell fate and targets drug resistance-related mechanisms
2019, Molecular Aspects of MedicineCitation Excerpt :Hypoxia, angiogenesis, EMT, invasion and metastasis regulation via miR-181 family. Angiogenesis is a multi-step signalling cascade that assists tumour advancement, growth, invasion and metastatic spread (Gulei et al., 2017; Tudoran et al., 2012). Formation of new blood vessels help cancer cells by providing them oxygen and nutrients and also represent one of the physical routes for their migration toward metastatic spots (Ionescu et al., 2014; Tudoran et al., 2012).
The extensive role of miR-155 in malignant and non-malignant diseases
2019, Molecular Aspects of MedicineCitation Excerpt :This pattern of expression is further associated with increased level of oncogenic target genes and reduced expression of target tumor suppressors coding transcripts. MiRNAs deregulation has been frequently associated with the activation of drug resistance genes (Reddy, 2015; Hayes et al., 2014; Gulei et al., 2017a, 2017b; Fabbri et al., 2008). Currently, numerous experimental studies investigate the modulation of specific miRNAs within the cancer cell to weaken the pathological phenotype and restore drug sensitivity within the cell.
Targeting ncRNAs by plant secondary metabolites: The ncRNAs game in the balance towards malignancy inhibition
2018, Biotechnology AdvancesCitation Excerpt :Moreover, this natural compound was able to modulate the miRNAs profile of pancreatic cancer cells, determining the increased expression of two important sequences: miR-200b and miR-200c. These two miRNAs are involved in key processes regarding epithelial to mesenchymal transition (EMT) (Gulei et al., 2017) and are often downregulated in pancreatic cancers, an event that influences the promotion of the mesenchymal phenotype with consequences on the advancement of metastasis. Another important aspect besides the anti-carcinogenic properties of CDF is represented by the superior action of this compound compared to curcumin, phytophenol recognized in the research area as an influential modulator of the carcinogenic process.
Combined Therapy in Cancer: The Non-coding Approach
2018, Molecular Therapy Nucleic Acids