{Reference Type}: Journal Article
{Title}: Tamoxifen metabolites treatment promotes ERα+ transition to triple negative phenotype in vitro, effects of LDL in chemoresistance.
{Author}: Muñoz-Ayala A;Chimal-Vega B;Serafín-Higuera N;Galindo-Hernández O;Ramírez-Rosales G;Córdova-Guerrero I;Gómez-Lucas LF;García-González V;
{Journal}: Biosci Rep
{Volume}: 44
{Issue}: 8
{Year}: 2024 Aug 28
{Factor}: 3.976
{DOI}: 10.1042/BSR20240444
{Abstract}: <B>OBJECTIVE: </B>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><B>METHODS: </B>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><B>RESULTS: </B>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><B>CONCLUSIONS: </B>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.