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Tamoxifen metabolites treatment promotes ERα+ transition to triple negative phenotype in vitro , effects of LDL in chemoresistance
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Tamoxifen metabolites treatment promotes ERα+ transition to triple negative phenotype in vitro , effects of LDL in chemoresistance
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Journal Article
Tamoxifen metabolites treatment promotes ERα+ transition to triple negative phenotype in vitro , effects of LDL in chemoresistance
2024
Overview
Objective: Estrogen receptor-positive (ER+) breast cancer represents about 80% of cases, tamoxifen is the election neoadjuvant chemotherapy. However, a large percentage of patients develop chemoresistance, compromising recovery. Clinical evidence suggests that high plasmatic levels of low-density lipoproteins (LDL) could promote cancer progression. The present study analyzed the effect of LDL on the primary plasmatic active Tamoxifen’s metabolites resistance acquisition, 4-hydroxytamoxifen (4OH-Tam) and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), in breast cancer ERα + cells (MCF-7). Methods: Two resistant cellular variants, MCF-7Var-H and MCF-7Var-I, were generated by a novel strategy and their phenotype features were evaluated. Phenotypic assessment was performed by MTT assays, cytometry, immunofluorescence microscopy, zymography and protein expression analysis. Results: MCF-7Var-H, generated only with tamoxifen metabolites, showed a critical down-regulation in hormone receptors, augmented migration capacity, metalloprotease 9 extracellular medium excretion, and a mesenchymal morphology in contrast with native MCF-7, suggesting the transition towards Triple-negative breast cancer (TNBC) phenotype. In contrast, MCF-7Var-I which was generated in a high LDL media, showed only a slight upregulation in ER and other less noticeable metabolic adaptations. Results suggest a potential role of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in phenotypic differences observed among variants. Conclusion: LDL high or low concentrations during Tamoxifen´s metabolites chemoresistance acquisition leads to different cellular mechanisms related to chemoresistance. A novel adaptative cellular response associated with Nrf2 activity could be implicated.
Publisher
Portland Press Ltd The Biochemical Society,Portland Press Ltd
Subject
Antineoplastic Agents, Hormonal - pharmacology
/ Breast Neoplasms - drug therapy
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Cancer
/ Cell Migration, Adhesion & Morphology
/ Cell Movement - drug effects
/ Drug Resistance, Neoplasm - drug effects
/ Estrogen Receptor alpha - genetics
/ Estrogen Receptor alpha - metabolism
/ Female
/ Gene Expression Regulation, Neoplastic - drug effects
/ Humans
/ Lipoproteins, LDL - metabolism
/ Molecular Bases of Health & Disease
/ Plasma
/ Tamoxifen - analogs & derivatives
/ Triple Negative Breast Neoplasms - drug therapy
/ Triple Negative Breast Neoplasms - metabolism
/ Triple Negative Breast Neoplasms - pathology
/ Tumors
