PMID- 31370818 OWN - NLM STAT- MEDLINE DCOM- 20200217 LR - 20231013 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 19 IP - 1 DP - 2019 Aug 1 TI - Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model. PG - 757 LID - 10.1186/s12885-019-5939-z [doi] LID - 757 AB - BACKGROUND: Doxorubicin is currently the most effective chemotherapeutic drug used to treat breast cancer. It has, however, been shown that doxorubicin can induce drug resistance resulting in poor patient prognosis and survival. Studies reported that the interaction between signalling pathways can promote drug resistance through the induction of proliferation, cell cycle progression and prevention of apoptosis. The aim of this study was therefore to determine the effects of doxorubicin on apoptosis signalling, autophagy, the mitogen-activated protein kinase (MAPK)- and phosphoinositide 3-kinase (PI3K)/Akt signalling pathway, cell cycle control, and regulators of the epithelial-mesenchymal transition (EMT) process in murine breast cancer tumours. METHODS: A tumour-bearing mouse model was established by injecting murine E0771 breast cancer cells, suspended in Hank's Balances Salt Solution and Corning(R) Matrigel(R) Basement Membrane Matrix, into female C57BL/6 mice. Fourty-seven mice were randomly divided into three groups, namely tumour control (received Hank's Balances Salt Solution), low dose doxorubicin (received total of 6 mg/ml doxorubicin) and high dose doxorubicin (received total of 15 mg/ml doxorubicin) groups. A higher tumour growth rate was, however, observed in doxorubicin-treated mice compared to the untreated controls. We therefore compared the expression levels of markers involved in cell death and survival signalling pathways, by means of western blotting and fluorescence-based immunohistochemistry. RESULTS: Doxorubicin failed to induce cell death, by means of apoptosis or autophagy, and cell cycle arrest, indicating the occurrence of drug resistance and uncontrolled proliferation. Activation of the MAPK/ extracellular-signal-regulated kinase (ERK) pathway contributed to the resistance observed in treated mice, while no significant changes were found with the PI3K/Akt pathway and other MAPK pathways. Significant changes were also observed in cell cycle p21 and DNA replication minichromosome maintenance 2 proteins. No significant changes in EMT markers were observed after doxorubicin treatment. CONCLUSIONS: Our results suggest that doxorubicin-induced drug resistance and tumour growth can occur through the adaptive role of the MAPK/ERK pathway in an effort to protect tumour cells. Previous studies have shown that the efficacy of doxorubicin can be improved by inhibition of the ERK signalling pathway and thereby treatment failure can be overcome. FAU - Christowitz, Claudia AU - Christowitz C AUID- ORCID: 0000-0002-4780-1978 AD - Department of Global Health, Faculty of Medicine and Health Sciences, African Cancer Institute, Stellenbosch University, Cape Town, 8000, South Africa. claudiac@sun.ac.za. FAU - Davis, Tanja AU - Davis T AD - Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, 7600, South Africa. FAU - Isaacs, Ashwin AU - Isaacs A AD - Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, 7600, South Africa. FAU - van Niekerk, Gustav AU - van Niekerk G AD - Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, 7600, South Africa. FAU - Hattingh, Suzel AU - Hattingh S AD - Department of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, 8000, South Africa. FAU - Engelbrecht, Anna-Mart AU - Engelbrecht AM AD - Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, 7600, South Africa. LA - eng GR - 99093/National Research Foundation/ PT - Journal Article DEP - 20190801 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Antineoplastic Agents) RN - 80168379AG (Doxorubicin) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Animals MH - Antineoplastic Agents/*therapeutic use MH - Apoptosis MH - Autophagy MH - Breast Neoplasms/*drug therapy MH - Cell Cycle MH - Cell Line, Tumor MH - Doxorubicin/*therapeutic use MH - Drug Resistance, Neoplasm MH - Epithelial-Mesenchymal Transition MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Female MH - Humans MH - Mice MH - Mice, Inbred C57BL MH - Phosphatidylinositol 3-Kinases/metabolism MH - Signal Transduction MH - Xenograft Model Antitumor Assays PMC - PMC6670209 OTO - NOTNLM OT - Breast cancer OT - Doxorubicin OT - Drug resistance OT - ERK OT - Signalling pathways OT - Tumour growth COIS- The authors declare that they have no competing interests. EDAT- 2019/08/03 06:00 MHDA- 2020/02/18 06:00 PMCR- 2019/08/01 CRDT- 2019/08/03 06:00 PHST- 2019/03/18 00:00 [received] PHST- 2019/07/15 00:00 [accepted] PHST- 2019/08/03 06:00 [entrez] PHST- 2019/08/03 06:00 [pubmed] PHST- 2020/02/18 06:00 [medline] PHST- 2019/08/01 00:00 [pmc-release] AID - 10.1186/s12885-019-5939-z [pii] AID - 5939 [pii] AID - 10.1186/s12885-019-5939-z [doi] PST - epublish SO - BMC Cancer. 2019 Aug 1;19(1):757. doi: 10.1186/s12885-019-5939-z.