Basma M Sharaf1,2, Alexander D Giddey2, Hamza M Al-Hroub2, Varsha Menon2, Javan Okendo3, Raafat El-Awady1,2, Muath Mousa4, Ahmed Almehdi5, Mohammad H Semreen6,7, Nelson C Soares8,9. 1. Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, P.O. Box. 27272, Sharjah, United Arab Emirates. 2. Research Institute for Medical and Health Sciences (RIHMS), University of Sharjah, Sharjah, United Arab Emirates. 3. Systems and Chemical Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road Observatory, Cape Town, 7925, South Africa. 4. Research Institute of Science and Engineering, University of Sharjah, Sharjah, United Arab Emirates. 5. Department of Chemistry, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates. 6. Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, P.O. Box. 27272, Sharjah, United Arab Emirates. msemreen@sharjah.ac.ae. 7. Research Institute for Medical and Health Sciences (RIHMS), University of Sharjah, Sharjah, United Arab Emirates. msemreen@sharjah.ac.ae. 8. Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, P.O. Box. 27272, Sharjah, United Arab Emirates. nsoares@sharjah.ac.ae. 9. Research Institute for Medical and Health Sciences (RIHMS), University of Sharjah, Sharjah, United Arab Emirates. nsoares@sharjah.ac.ae.
Abstract
PURPOSE: HER2-enriched breast cancer with high levels of hormone receptor expression, known as "triple positive" breast cancer, may represent a new entity with a relatively favourable prognosis against which the combination of chemotherapy, HER-2 inhibition, and endocrine treatment may be considered overtreatment. We explored the effect of the anticancer drugs tamoxifen and trastuzumab, both separately and in combination, on the integrated proteomic and metabolic profile of "triple positive" breast cancer cells (BT-474). METHOD: We employed ultra-high-performance liquid chromatography-quadrupole time of flight mass spectrometry using a Bruker timsTOF to investigate changes in BT-474 cell line treated with either tamoxifen, trastuzumab or a combination. Differentially abundant metabolites were identified using the Bruker Human Metabolome Database metabolite library and proteins using the Uniprot proteome for Homo sapiens using MetaboScape and MaxQuant, respectively, for identification and quantitation. RESULTS: A total of 77 proteins and 85 metabolites were found to significantly differ in abundance in BT-474 treated cells with tamoxifen 5 μM/and or trastuzumab 2.5 μM. Findings suggest that by targeting important cellular signalling pathways which regulate cell growth, apoptosis, proliferation, and chemoresistance, these medicines have a considerable anti-growth effect in BT-474 cells. Pathways enriched for dysregulation include RNA splicing, neutrophil degranulation and activation, cellular redox homeostasis, mitochondrial transmembrane transport, ferroptosis and necroptosis, ABC transporters and central carbon metabolism. CONCLUSION: Our findings in protein and metabolite level research revealed that anti-cancer drug therapy had a significant impact on the key signalling pathways and molecular processes in triple positive BT-474 cell lines.
PURPOSE: HER2-enriched breast cancer with high levels of hormone receptor expression, known as "triple positive" breast cancer, may represent a new entity with a relatively favourable prognosis against which the combination of chemotherapy, HER-2 inhibition, and endocrine treatment may be considered overtreatment. We explored the effect of the anticancer drugs tamoxifen and trastuzumab, both separately and in combination, on the integrated proteomic and metabolic profile of "triple positive" breast cancer cells (BT-474). METHOD: We employed ultra-high-performance liquid chromatography-quadrupole time of flight mass spectrometry using a Bruker timsTOF to investigate changes in BT-474 cell line treated with either tamoxifen, trastuzumab or a combination. Differentially abundant metabolites were identified using the Bruker Human Metabolome Database metabolite library and proteins using the Uniprot proteome for Homo sapiens using MetaboScape and MaxQuant, respectively, for identification and quantitation. RESULTS: A total of 77 proteins and 85 metabolites were found to significantly differ in abundance in BT-474 treated cells with tamoxifen 5 μM/and or trastuzumab 2.5 μM. Findings suggest that by targeting important cellular signalling pathways which regulate cell growth, apoptosis, proliferation, and chemoresistance, these medicines have a considerable anti-growth effect in BT-474 cells. Pathways enriched for dysregulation include RNA splicing, neutrophil degranulation and activation, cellular redox homeostasis, mitochondrial transmembrane transport, ferroptosis and necroptosis, ABC transporters and central carbon metabolism. CONCLUSION: Our findings in protein and metabolite level research revealed that anti-cancer drug therapy had a significant impact on the key signalling pathways and molecular processes in triple positive BT-474 cell lines.
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