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Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development
To prevent the development of endocrine-resistant breast cancer, additional targeted therapies are increasingly being trialled in combination with endocrine therapy. The molecular mechanisms facilitating cancer cell survival during endocrine treatment remain unknown but could help direct selection o...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9935392/ https://www.ncbi.nlm.nih.gov/pubmed/36266450 http://dx.doi.org/10.1038/s41417-022-00548-0 |
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author | Madden, Stephen F. Cremona, Mattia Farrelly, Angela M. Low, Weng Hei McBryan, Jean |
author_facet | Madden, Stephen F. Cremona, Mattia Farrelly, Angela M. Low, Weng Hei McBryan, Jean |
author_sort | Madden, Stephen F. |
collection | PubMed |
description | To prevent the development of endocrine-resistant breast cancer, additional targeted therapies are increasingly being trialled in combination with endocrine therapy. The molecular mechanisms facilitating cancer cell survival during endocrine treatment remain unknown but could help direct selection of additional targeted therapies. We present a novel proteomic timecourse dataset, profiling potential drug targets in a population of MCF7 cells during 1 year of tamoxifen treatment. Reverse phase protein arrays profiled >70 proteins across 30 timepoints. A biphasic response to tamoxifen was evident, which coincided with changes in growth rate. Tamoxifen strongly impeded cell growth for the first 160 days, followed by gradual growth recovery and eventual resistance development. The growth-impeded phase was distinguished by the phosphorylation of Stat3 (y705) and Src (y527). Tumour tissue from patients treated with neo-adjuvant endocrine therapy (<4 months) also displayed increased Stat3 and Src signalling. Inhibitors of Stat3 (napabucasin) and Src (dasatinib), were effective at killing tamoxifen-treated MCF7 and T47D cells. Sensitivity to both drugs was significantly enhanced once tamoxifen had induced the growth-impeded phase. This novel proteomic resource identifies key mechanisms enabling cell survival during tamoxifen treatment. It provides valuable insight into potential drug combinations and timing that may prevent the development of endocrine resistance. |
format | Online Article Text |
id | pubmed-9935392 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-99353922023-02-18 Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development Madden, Stephen F. Cremona, Mattia Farrelly, Angela M. Low, Weng Hei McBryan, Jean Cancer Gene Ther Article To prevent the development of endocrine-resistant breast cancer, additional targeted therapies are increasingly being trialled in combination with endocrine therapy. The molecular mechanisms facilitating cancer cell survival during endocrine treatment remain unknown but could help direct selection of additional targeted therapies. We present a novel proteomic timecourse dataset, profiling potential drug targets in a population of MCF7 cells during 1 year of tamoxifen treatment. Reverse phase protein arrays profiled >70 proteins across 30 timepoints. A biphasic response to tamoxifen was evident, which coincided with changes in growth rate. Tamoxifen strongly impeded cell growth for the first 160 days, followed by gradual growth recovery and eventual resistance development. The growth-impeded phase was distinguished by the phosphorylation of Stat3 (y705) and Src (y527). Tumour tissue from patients treated with neo-adjuvant endocrine therapy (<4 months) also displayed increased Stat3 and Src signalling. Inhibitors of Stat3 (napabucasin) and Src (dasatinib), were effective at killing tamoxifen-treated MCF7 and T47D cells. Sensitivity to both drugs was significantly enhanced once tamoxifen had induced the growth-impeded phase. This novel proteomic resource identifies key mechanisms enabling cell survival during tamoxifen treatment. It provides valuable insight into potential drug combinations and timing that may prevent the development of endocrine resistance. Nature Publishing Group US 2022-10-20 2023 /pmc/articles/PMC9935392/ /pubmed/36266450 http://dx.doi.org/10.1038/s41417-022-00548-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Madden, Stephen F. Cremona, Mattia Farrelly, Angela M. Low, Weng Hei McBryan, Jean Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development |
title | Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development |
title_full | Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development |
title_fullStr | Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development |
title_full_unstemmed | Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development |
title_short | Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development |
title_sort | proteomic time course of breast cancer cells highlights enhanced sensitivity to stat3 and src inhibitors prior to endocrine resistance development |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9935392/ https://www.ncbi.nlm.nih.gov/pubmed/36266450 http://dx.doi.org/10.1038/s41417-022-00548-0 |
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