Back to Search
Start Over
Tamoxifen metabolites treatment promotes ERα+ transition to triple negative phenotype in vitro, effects of LDL in chemoresistance.
- Source :
-
Bioscience reports [Biosci Rep] 2024 Aug 28; Vol. 44 (8). - Publication Year :
- 2024
-
Abstract
- 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).<br />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.<br />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.<br />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.<br /> (© 2024 The Author(s).)
- Subjects :
- Humans
MCF-7 Cells
Female
Antineoplastic Agents, Hormonal pharmacology
Cell Movement drug effects
Breast Neoplasms drug therapy
Breast Neoplasms metabolism
Breast Neoplasms pathology
Gene Expression Regulation, Neoplastic drug effects
Tamoxifen pharmacology
Tamoxifen analogs & derivatives
Drug Resistance, Neoplasm drug effects
Estrogen Receptor alpha metabolism
Estrogen Receptor alpha genetics
Triple Negative Breast Neoplasms drug therapy
Triple Negative Breast Neoplasms metabolism
Triple Negative Breast Neoplasms pathology
Lipoproteins, LDL metabolism
Phenotype
Subjects
Details
- Language :
- English
- ISSN :
- 1573-4935
- Volume :
- 44
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Bioscience reports
- Publication Type :
- Academic Journal
- Accession number :
- 39034849
- Full Text :
- https://doi.org/10.1042/BSR20240444