Lactate is a potential promoter of tamoxifen resistance in MCF7 cells

• Published in: Biochimica et biophysica acta. General subjects 2022-09, Vol.1866 (9), p.130185-130185, Article 130185
• Main Authors: Rossi, Valentina, Govoni, Marzia, Farabegoli, Fulvia, Di Stefano, Giuseppina
• Format: Article
• Language: English
• Subjects: Breast cancer; Drug resistance; Glycolysis; Lactate; Tamoxifen
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2022.130185

Tamoxifen is a widely used estrogen receptor inhibitor, whose clinical success is limited by the development of acquired resistance. This compound was also found to inhibit mitochondrial function, causing increased glycolysis and lactate production. Lactate has been widely recognized as a signaling molecule, showing the potential of modifying gene expression. These metabolic effects of tamoxifen can by hypothesized to contribute in driving drug resistance. To test this hypothesis, we used MCF7 cells together with a tamoxifen resistant cell line (MCF7-TAM). Experiments were aimed at verifying whether enhanced lactate exposure can affect the phenotype of MCF7 cells, conferring them features mirroring those observed in the tamoxifen resistant culture. The obtained results suggested that enhanced lactate in MCF7 cells medium can increase the expression of tafazzin (TAZ) and telomerase complex (TERC, TERT) genes, reducing the cells' attitude to undergo senescence. In long term lactate-exposed cells, signs of EGFR activation, a pathway related to acquired tamoxifen resistance, was also observed. The obtained results suggested lactate as a potential promoter of tamoxifen resistance. The off-target effects of this compound could play a role in hindering its therapeutic efficacy. The features of acquired tamoxifen resistance have been widely characterized at the molecular level; in spite of their heterogeneity, poorly responsive cells were often found to display upregulated glycolysis. Our results suggest that this metabolic asset is not simply a result of neoplastic progression, but can play an active part in driving this process. [Display omitted] •Tamoxifen is the first-choice drug in the adjuvant therapy of ER+ breast cancer.•About 30% treated patients develop acquired resistance to tamoxifen treatment.•Tamoxifen shows off-target effects resulting in increased lactate production.•Increased lactate production can contribute to the acquired tamoxifen resistance.