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      The fate of chemoresistance in triple negative breast cancer (TNBC)

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          Abstract

          Background

          Treatment options for women presenting with triple negative breast cancer (TNBC) are limited due to the lack of a therapeutic target and as a result, are managed with standard chemotherapy such as paclitaxel (Taxol®).

          Following chemotherapy, the ideal tumour response is apoptotic cell death. Post-chemotherapy, cells can maintain viability by undergoing viable cellular responses such as cellular senescence, generating secretomes which can directly enhance the malignant phenotype.

          Scope of Review

          How tumour cells retain viability in response to chemotherapeutic engagement is discussed. In addition we discuss the implications of this retained tumour cell viability in the context of the development of recurrent and metastatic TNBC disease.

          Current adjuvant and neo-adjuvant treatments available and the novel potential therapies that are being researched are also reviewed.

          Major conclusions

          Cellular senescence and cytoprotective autophagy are potential mechanisms of chemoresistance in TNBC. These two non-apoptotic outcomes in response to chemotherapy are inextricably linked and are neglected outcomes of investigation in the chemotherapeutic arena. Cellular fate assessments may therefore have the potential to predict TNBC patient outcome.

          General Significance

          Focusing on the fact that cancer cells can bypass the desired cellular apoptotic response to chemotherapy through cellular senescence and cytoprotective autophagy will highlight the importance of targeting non-apoptotic survival pathways to enhance chemotherapeutic efficacy.

          Highlights

          • How tumour cells retain viability after chemotherapeutic engagement is discussed.

          • The implications of tumour cell viability in TNBC are discussed.

          • Chemotherapy and novel therapies that are currently being researched are reviewed.

          • Chemoresistance mechanisms and hypoxia’s role in TNBC are outlined.

          • Senescence and autophagy are potential mechanisms of chemoresistance in TNBC.

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          Most cited references180

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          Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.

          PURPOSE Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR. CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.
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            Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.

            Autophagy is a process by which cytoplasmic organelles can be catabolized either to remove defective structures or as a means of providing macromolecules for energy generation under conditions of nutrient starvation. In this study we demonstrate that mitochondrial autophagy is induced by hypoxia, that this process requires the hypoxia-dependent factor-1-dependent expression of BNIP3 and the constitutive expression of Beclin-1 and Atg5, and that in cells subjected to prolonged hypoxia, mitochondrial autophagy is an adaptive metabolic response which is necessary to prevent increased levels of reactive oxygen species and cell death.
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              Tumour biology: senescence in premalignant tumours.

              Oncogene-induced senescence is a cellular response that may be crucial for protection against cancer development, but its investigation has so far been restricted to cultured cells that have been manipulated to overexpress an oncogene. Here we analyse tumours initiated by an endogenous oncogene, ras, and show that senescent cells exist in premalignant tumours but not in malignant ones. Senescence is therefore a defining feature of premalignant tumours that could prove valuable in the diagnosis and prognosis of cancer.
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                Author and article information

                Contributors
                Journal
                BBA Clin
                BBA Clin
                BBA Clinical
                Elsevier
                2214-6474
                12 March 2015
                June 2015
                12 March 2015
                : 3
                : 257-275
                Affiliations
                [a ]UCD Conway Institute of Biomolecular and Biomedical Research, UCD School of Medicine and Medical Science (SMMS), Belfield, Dublin 4, Ireland
                [b ]Department of Surgery, Mater Misericordiae Hospital, Dublin 7, Ireland
                [c ]Department of Oncology, Mater Misericordiae Hospital, Dublin 7, Ireland
                [d ]Department of Pathology, Mater Misericordiae Hospital, Dublin 7, Ireland
                [e ]School of Pharmacy, Queens University Belfast, Belfast BT7 1NN, UK
                Author notes
                [* ]Corresponding author at: UCD Conway Institute of Biomolecular and Biomedical Research, UCD School of Medicine and Medical Science (SMMS), Belfield, Dublin 4, Ireland. Tel.: + 353 879083394. elmaannaoreilly@ 123456gmail.com
                Article
                S2214-6474(15)00017-3
                10.1016/j.bbacli.2015.03.003
                4661576
                26676166
                da0ef0c0-ba1d-4bef-b39b-80943a259843
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 December 2014
                : 3 March 2015
                : 5 March 2015
                Categories
                Review

                triple negative breast cancer (tnbc),cellular fates,cellular senescence,chemoresistance,hypoxia

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