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Tamoxifen-Induced Apoptosis of MCF-7 Cells via GPR30/PI3K/MAPKs Interactions: Verification by ODE Modeling and RNA
Milad Rouhimoghadam1, Shahrokh Safarian1, Jason S Carroll2
1Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
Abstract:
Tamoxifen (Nolvadex) is one of the most widely used and effective therapeutic agent for breast cancer. It benefits nearly 75% of patients with estrogen receptor (ER)-positive breast cancer that receive this drug. Its effectiveness is mainly attributed to its capacity to function as an ER antagonist, blocking estrogen binding sites on the receptor, and inhibiting the proliferative action of the receptor-hormone complex. Although, tamoxifen can induce apoptosis in breast cancer cells via upregulation of pro-apoptotic factors, it can also promote uterine hyperplasia in some women. Thus, tamoxifen as a multi-functional drug could have different effects on cells based on the utilization of effective concentrations or availability of specific co-factors. Evidence that tamoxifen functions as a GPR30 (G-Protein Coupled Receptor 30) agonist activating adenylyl cyclase and EGFR (Epidermal Growth Factor Receptor) intracellular signaling networks, provides yet another means of explaining the multi-functionality of tamoxifen. Here ordinary differential equation (ODE) modeling, RNA sequencing and real time qPCR analysis were utilized to establish the necessary data for gene network mapping of tamoxifen-stimulated MCF-7 cells, which express the endogenous ER and GPR30. The gene set enrichment analysis and pathway analysis approaches were used to categorize transcriptionally upregulated genes in biological processes. Of the 2,713 genes that were significantly upregulated following a 48 h incubation with 250 microM tamoxifen, most were categorized as either growth-related or pro-apoptotic intermediates that fit into the Tp53 and/or MAPK signaling pathways. Collectively, our results display that the effects of tamoxifen on the breast cancer MCF-7 cell line are mediated by the activation of important signaling pathways including Tp53 and MAPKs to induce apoptosis.
Insights
Tamoxifen, a breast cancer drug, activates Tp53 and MAPK pathways in MCF-7 cells. This leads to the upregulation of genes that promote cancer cell apoptosis, offering a new understanding of tamoxifen
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Tamoxifen is a widely used breast cancer therapeutic, primarily benefiting estrogen receptor (ER)-positive patients by acting as an ER antagonist.
- Tamoxifen's multi-functional effects may stem from its roles as an ER antagonist and a G-Protein Coupled Receptor 30 (GPR30) agonist, influencing intracellular signaling pathways like EGFR.
- The drug's cellular effects can vary based on concentration and co-factor availability, necessitating a deeper understanding of its molecular mechanisms.
Purpose of the Study:
- To investigate the gene network and signaling pathways modulated by tamoxifen in ER- and GPR30-expressing breast cancer cells (MCF-7).
- To elucidate the molecular mechanisms underlying tamoxifen's pro-apoptotic and growth-related effects.
- To map the transcriptional changes induced by tamoxifen in a relevant cellular model.
Main Methods:
- Ordinary differential equation (ODE) modeling was employed to analyze gene expression dynamics.
- RNA sequencing and real-time quantitative PCR (qPCR) were utilized to identify and quantify gene expression changes.
- Gene set enrichment analysis and pathway analysis were performed to categorize upregulated genes and identify key biological processes and signaling pathways.
Main Results:
- Tamoxifen significantly upregulated 2,713 genes in MCF-7 cells after 48 hours of incubation with 250 microM concentration.
- The majority of upregulated genes were associated with growth-related processes or pro-apoptotic functions.
- Key signaling pathways identified as significantly modulated by tamoxifen include Tp53 and MAPK signaling pathways.
Conclusions:
- Tamoxifen's effects on MCF-7 breast cancer cells are mediated through the activation of critical signaling pathways, notably Tp53 and MAPKs.
- These activated pathways contribute to the induction of apoptosis in breast cancer cells.
- The study provides a comprehensive gene network map, enhancing the understanding of tamoxifen's therapeutic action at a molecular level.
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