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Alterations of Genetic Variants and Transcriptomic Features of Response to Tamoxifen in the Breast Cancer Cell Line

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Alterations of Genetic Variants and Transcriptomic Features of Response to Tamoxifen in the Breast Cancer Cell Line Mahnaz Nezamivand-Chegini Shiraz University Hamed Kharrati-Koopaee Shiraz University https://orcid.org/0000-0003-2345-6919 seyed taghi Heydari ( [email protected] ) Shiraz University of Medical Sciences https://orcid.org/0000-0001-7711-1137 Hasan Giahi Shiraz University Ali Dehshahri Shiraz University of Medical Sciences Mehdi Dianatpour Shiraz University of Medical Sciences Kamran Bagheri Lankarani Shiraz University of Medical Sciences Research Keywords: Tamoxifen, breast cancer, genetic variants, RNA-seq. Posted Date: August 17th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-783422/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/33 Abstract Background Breast cancer is one of the most important causes of mortality in the world, and Tamoxifen therapy is known as a medication strategy for estrogen receptor-positive breast cancer. In current study, two hypotheses of Tamoxifen consumption in breast cancer cell line (MCF7) were investigated. First, the effect of Tamoxifen on genes expression prole at transcriptome level was evaluated between the control and treated samples. Second, due to the fact that Tamoxifen is known as a mutagenic factor, there may be an association between the alterations of genetic variants and Tamoxifen treatment, which can impact on the drug response. Methods In current study, the whole-transcriptome (RNA-seq) dataset of four investigations (19 samples) were derived from European Bioinformatics Institute (EBI). At transcriptome level, the effect of Tamoxifen was investigated on gene expression prole between control and treatment samples. Moreover, Tamoxifen is known as a mutagenic factor, therefore, its contribution to alterations of genetic variants and drug response were examined. Results Results achieved from RNA-seq analysis indicated the contribution of several candidate genes to tumor suppression process and consequently, the achievement of an effective treatment. For instance, XIAP- associated factor 1 (XAF1) was reported as an up-regulated gene under Tamoxifen therapy. XAF1 is a tumor suppressor that contributes to the apoptosis induction and tumor growth inhibition along with TP53. Results of gene ontology enrichment analysis of differential gene expressions indicated that most of them could considerably lead to the cell death, apoptosis, and negative regulation of proteolysis process. Findings achieved from evaluating Tamoxifen mutagenicity effect on drug response was not conrmed perfectly. The most reported candidate genes, which were related to differential genetic variants between control and treated samples, played the oncogene and tumor suppressor dual roles and also their exact roles in breast cancer were not investigated precisely. Conclusion At transcriptome level, Tamoxifen consumption in MCF7 cell line could be associated with candidate genes and biological pathways that contribute to the apoptosis, proteolysis, and tumor suppression. The mutagenicity effect of Tamoxifen and its contribution to drug response was not conrmed perfectly. Page 2/33 Background Cancer is one of the most important causes of mortality in the world and breast cancer is a common disease among women. Hormonal therapy is a medical strategy for breast cancer treatment ( Akram et al. 2017). Tamoxifen is considered as the main non-steroidal drug in breast cancer treatment for postmenopausal women (Abo-Touk et al. 2010), which inhibits the estrogen activity through binding to the estrogen receptor competitively (Geisler, 2011). There are several investigations carried out with the purpose of illustrating the hormonal therapy effects that provide a better understanding of the drug response mechanism and select an effective strategy for the therapeutic period (AlFakeeh and Brezden-Masley, 2018; Szostakowska et al. 2019; Fan et al. 2015; Moiseenko et al. 2017). The appropriate drug response is a complex interdependent procedure that is highly dependent upon several factors including the genetic variants background, lifestyle, climate, smoking, and alcohol consumption (Levy and Polatsek, 2002; Bachtiar and Lee. 2013). Genetic variants refer to the genetic differences between individuals of a population (Kharrati et al., 2012). DNA is a vulnerable molecule against various mutagens including ultraviolet, toxins, chemical agent, and free radicals (Koopaee and Esmailizadeh, 2014). Recently, high-throughput sequencing platforms have been applied as powerful tools in order to investigate the association between a massive number of genetic variants and drug response (Madian et al. 2012; Esfandiari et al., 2020). It is shown that Tamoxifen has a mutagenic effect on the endometrium cells and increases the incidence of endometrial tumors (White and Smith, 1996). Results of evaluating the rat hepatic tissue showed that activated Tamoxifen could bind to guanine N2-position of DNA and consequently, produce pro-mutagenic lesion (Brown, 2009). More importantly, it was found that Tamoxifen mutagenicity effect induced DNA damages in human endometrial cells (Liapis et al., 2008). Considering the in vitro conditions, Tamoxifen would lead to the gene mutations and increased incidence of abnormal chromosomal structures in rat liver tissues (Davies et al., 1997). All of the above-mentioned literature reviews indicated that Tamoxifen could play a critical role in the alterations of genetic variants background. There are several examples about the role of genetic variants in drug response. To achieve a therapeutic effect, there has to be an interaction between the drug and its target. DNA variations can both increase and decrease the binding anity of a drug to its target. In addition, genetic variations can transform the antagonist role of drug into an agonist one; therefore, the most common problem of treatment procedures is resistant mutations in drug targets. Tamoxifen blackens Estrogen (ER-positive cancer) in the breast cancer treatment procedure and consequently, decreases the risk of cancer recurrence. Tamoxifen is an anti-estrogen hormone that inhibits the Estrogen receptors; however, its eciency would be decreased as a result of the occurrence of mutations in estrogen receptors and it leads to the conversion of RE-positive into progesterone-positive cancer. Consequently, it causes the drug resistance development and nonresponse to treatment (Wardell et al. 2019). It is noteworthy that genetic variations may contribute to drug metabolism and inuence the drug response. For instance, if the drug is rapidly metabolized, its concentration will decrease due to the Page 3/33 weaker drug action or side effects. Considering slower metabolism procedures, higher drug levels would result in the stronger or longer actions and side effects (Levy and Polatsek, 2002). Gene expression analysis at transcriptome level is considered as another considerable tool that can show the effects of hormone therapy on genes expression proles. It has been shown through several studies that there is a close association between transcriptome response and therapeutic drug consumption (Sjöström et al., 2020; Fekete et al., 2019; Men et al., 2018; Kumari et al., 2017 and Selli et al., 2016). It was found from one of the main investigations that carried out a comprehensive transcriptomic analysis on Tamoxifen resistance that ncRNAs proling breast cancer cells would provide a new light on the identication of novel endocrine resistance biomarkers (Gao et al., 2020). Lanceta et al. (2020) carried out RNA sequencing (RNA-seq) and pathway analysis in ER + MCF7, and reported 2183 up-regulated and 1548 down-regulated transcripts that contributed to cell cycle, DNA replication, and DNA repair and autophagy. Current study investigates two hypotheses of Tamoxifen consumption in breast cancer cell line (MCF7). First, there may be an association between genetic variants alterations and Tamoxifen treatment due to the fact that Tamoxifen is a mutagenic factor that impacts on the drug response. Second, how does Tamoxifen affect the gene expression prole at transcriptome level? Investigating Tamoxifen therapy- changed genetic variants and genes expression could be useful to understand the drug response mechanism; also, it would provide a new insight to the increase of the chance of survival, decrease the side effects, and select an appropriate strategy for the therapy period. 2. Materials The summary of data collections, genetic variant, and RNA-seq analyses are represented in Figure 1. 2.1 Data collection In current study, the whole-transcriptome (RNA-seq) dataset of four investigations were derived from EBI (https://www.ebi.ac.uk/). More details of collected datasets were provided in Table1. Table1. More details of RNA-seq datasets to discover the genetic variants and gene expression analysis Accession number Control samples Treatment samples Drug type Cell line E-MTAB-822 1 2 Tamoxifen MCF7 E-GEOD-59536 1 1 Tamoxifen MCF7 E-GEOD-62613 1 1 Tamoxifen MCF7 E-GEOD-78199 6 6 Tamoxifen MCF7 Total 9 10 ---- ---- 2.2 Quality control and trimming Page 4/33 It was observed that various parameters led to the appropriate quality control functions in CLC Genomic Workbench (12) for each sample including length distribution, GC content, ambiguous base content, Phred score, nucleotide contribution, enrich 5 mers, and duplicate sequences (Kharrati-Koopaee et al., 2019). Due to the fact that the adaptor
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