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      Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge

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          Abstract

          Triple-negative (TNBC) is the most lethal subtype of breast cancer owing to high heterogeneity, aggressive nature, and lack of treatment options. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance. Accordingly, in recent years, tremendous effort has been made into elucidating the mechanisms of TNBC chemoresistance with the goal of identifying new molecular targets. It has become evident that the development of TNBC chemoresistance is multifaceted and based on the elaborate interplay of the tumor microenvironment, drug efflux, cancer stem cells, and bulk tumor cells. Alterations of multiple signaling pathways govern these interactions. Moreover, TNBC’s high heterogeneity, highlighted in the existence of several molecular signatures, presents a significant obstacle to successful treatment. In the present, in-depth review, we explore the contribution of key mechanisms to TNBC chemoresistance as well as emerging strategies to overcome them. We discuss novel anti-tumor agents that target the components of these mechanisms and pay special attention to their current clinical development while emphasizing the challenges still ahead of successful TNBC management. The evidence presented in this review outlines the role of crucial pathways in TNBC survival following chemotherapy treatment and highlights the importance of using combinatorial drug strategies and incorporating biomarkers in clinical studies.

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          Most cited references127

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          Latent TGF-β structure and activation.

          Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of α(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between α(v)β(6) integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.
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            XBP1 Promotes Triple Negative Breast Cancer By Controlling the HIF1 α Pathway

            Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization 1 . One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 2 and its substrate XBP1 3 . Previous studies report UPR activation in various human tumors 4-6 , but XBP1's role in cancer progression in mammary epithelial cells is largely unknown. Triple negative breast cancer (TNBC), a form of breast cancer in which tumor cells do not express the genes for estrogen receptor, progesterone receptor, and Her2/neu, is a highly aggressive malignancy with limited treatment options 7, 8 . Here, we report that XBP1 is activated in TNBC and plays a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumor growth and tumor relapse and reduced the CD44high/CD24low population. Hypoxia-inducing factor (HIF)1α is known to be hyperactivated in TNBCs 9, 10 . Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and imply that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
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              The Varied Roles of Notch in Cancer.

              Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after briefly reviewing new insights into physiologic mechanisms of Notch signaling in healthy tissues and defects in Notch signaling that contribute to congenital disorders and viral infection, we discuss the varied roles of Notch in cancer, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                22 August 2019
                September 2019
                : 8
                : 9
                Affiliations
                Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
                Author notes
                [* ]Correspondence: mnedel30@ 123456yahoo.co.uk ; Tel.: +381-112067100
                Article
                cells-08-00957
                10.3390/cells8090957
                6770896
                31443516
                f1cd50f1-7d93-4343-b523-44e06080e85a
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Review

                triple-negative breast cancer,chemoresistance,abc transporters,cancer stem cells,signaling pathways,hypoxia,apoptosis,receptor tyrosine kinases,microrna,molecular subtypes

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