Review
The “good-cop bad-cop” TGF-beta role in breast cancer modulated by non-coding RNAs

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Highlights

  • TGFß is actively involved in the preservation of balance within the immune system in order to avoid the installation of autoimmune diseases but in the same time maintain the effective level of defense against pathogens

  • TGFß is responsible for tumor suppression in the early steps of carcinogenesis, by supporting apoptosis and inhibiting cell proliferation. However, mutation acquisition in other pathways, along with the progression of carcinogenesis, endows TGFß with tumor-promoting roles

  • TGFβ-induced EMT 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 encourages cancer progression and metastasis

  • Numerous miRNAs and lncRNAs are involved in TGFβ signaling and EMT regulation through direct targeting of specific transcription factors. Special attention is granted towards miR-200 and miR-34 families

Abstract

Background

Lack of early diagnosis methods and the development of drug resistance are among the main reasons for increased mortality rates within breast cancer patients. These two aspects are governed by specific pro-carcinogenic modifications, where TGBβ-induced EMT is one of the leading actors. Endowment of the epithelial cells with mesenchymal characteristics allows them to migrate and invade secondary tissues in order to form malignant sites and also confers chemoresistance. TGFβ which role switches from the tumor suppressor cytokine to the oncogenic one favoring the tumor microenvironment regulates this process.

Scope of review

This review aims to comprehensively present the updated TGFβ-induced EMT in breast cancer, including the regulatory role of the non-coding RNAs with focus on the miR-200 family and newly discovered lncRNAs such as HOTAIRM1. Additionally, a new phenotype, P-EMT, also modulated by miR-200 and miR-34 families that form complex feedback loops with TGFβ, SNAI1 and ZEB1/2 is presented under an updated form.

Major conclusions

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, inhibition of EMT could represent an important milestone in mammary cancer treatment.

General significance

The present review assembles the most recent data regarding TGFβ induced EMT, including the input of non-coding RNAs, contributing to the possible development of new targeted treatment strategies for cancer patients.

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

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.

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