PPARγ antagonism as a new tool for preventing or overcoming endocrine resistance in luminal A breast cancers.

Purpose: This research investigates the role of PPARγ in the complex molecular events underlying the acquisition of resistance to tamoxifen (Tam) in luminal A breast cancer (BC) cells. Furthermore, it focuses on evaluating the possibility of repurposing Imatinib mesylate, an FDA-approved anticancer agent recently recognized also as a PPARγ antagonist, for the personalized therapy of endocrine-resistant BC with increased PPARγ expression.
Methods: Differential gene expression between parental and Tam-resistant MCF7 cells was assessed by RNA-seq followed by bioinformatics analysis and validation by RT-qPCR. PPARγ was downregulated by esiRNAs or inhibited by the antagonist GW9662. Cell viability and proliferation were measured by MTT and colony formation assays. Spheroids were prepared from parental and Tam-resistant MCF7 cells. Other luminal A BC cell lines resistant to Tam were generated.
Results: In MCF7-TamR cells, PPARγ and several of its target genes were significantly upregulated. Increased PPARγ expression was due to the modulation of its positive/negative transcriptional regulators. Downregulating PPARγ with esiRNAs or GW9662 effectively killed parental and Tam-resistant cells and spheroids. Imatinib revealed to be as effective as GW9662 in restoring Tam susceptibility of these cells. PPARγ overexpression was also observed in the newly-selected Tam-resistant luminal A BC cells, in which GW9662 and Imatinib restored their susceptibility to Tam.
Conclusion: Our findings demonstrate that the overexpression of PPARγ is a frequent occurrence during acquisition of Tam resistance in luminal A BC cells, and that PPARγ antagonism represents an alternative therapeutic approach for the personalized treatment of BC showing dysregulation of this nuclear receptor.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)