Activating transcription factor-2 (ATF2) is a key determinant of resistance to endocrine treatment in an in vitro model
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RESEARCH ARTICLE
Open Access
Activating transcription factor-2 (ATF2) is a key determinant of resistance to endocrine treatment in an in vitro model of breast cancer Athina Giannoudis1,2†, Mohammed Imad Malki1†, Bharath Rudraraju1,3†, Hisham Mohhamed4, Suraj Menon5, Triantafillos Liloglou1, Simak Ali3, Jason S. Carroll5 and Carlo Palmieri1,2*
Abstract Background: Activating transcription factor-2 (ATF2), a member of the leucine zipper family of DNA binding proteins, has been implicated as a tumour suppressor in breast cancer. However, its exact role in breast cancer endocrine resistance is still unclear. We have previously shown that silencing of ATF2 leads to a loss in the growthinhibitory effects of tamoxifen in the oestrogen receptor (ER)-positive, tamoxifen-sensitive MCF7 cell line and highlighted that this multi-faceted transcription factor is key to the effects of tamoxifen in an endocrine sensitive model. In this work, we explored further the in vitro role of ATF2 in defining the resistance to endocrine treatment. Materials and methods: We knocked down ATF2 in TAMR, LCC2 and LCC9 tamoxifen-resistant breast cancer cell lines as well as the parental tamoxifen sensitive MCF7 cell line and investigated the effects on growth, colony formation and cell migration. We also performed a microarray gene expression profiling (Illumina Human HT12_v4) to explore alterations in gene expression between MCF7 and TAMRs after ATF2 silencing and confirmed gene expression changes by quantitative RT-PCR. Results: By silencing ATF2, we observed a significant growth reduction of TAMR, LCC2 and LCC9 with no such effect observed with the parental MCF7 cells. ATF2 silencing was also associated with a significant inhibition of TAMR, LCC2 and LCC9 cell migration and colony formation. Interestingly, knockdown of ATF2 enhanced the levels of ER and ER-regulated genes, TFF1, GREB1, NCOA3 and PGR, in TAMR cells both at RNA and protein levels. Microarray gene expression identified a number of genes known to mediate tamoxifen resistance, to be differentially regulated by ATF2 in TAMR in relation to the parental MCF7 cells. Moreover, differential pathway analysis confirmed enhanced ER activity after ATF2 knockdown in TAMR cells. (Continued on next page)
* Correspondence: [email protected] † Athina Giannoudis, Mohammed Imad Malki and Bharath Rudraraju contributed equally to this work. 1 Department of Molecular and Clinical Cancer Medicine, The Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, UK 2 The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK Full list of author information is available at the end of the article © The Author(s). 2020 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 t
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