Actin-regulated plasticity as a key determinant of the bidirectional switch between chemoresistance and resensitization in triple-positive breast cancer.

[AIM] Tamoxifen-induced chemoresistance promotes cancer cell survival, progression, and metastasis. Therefore, we investigated and validated tamoxifen resistance involvement in cancer progression.

[METHODS] Tamoxifen resistance was induced in MCF7 cells; subsequently, fluorescence microscopy and proteomics were used to assess actin-mediated cellular alterations. Moreover, in vitro (cell migration and invasion assays) and in vivo tumor assays were used to assess the role of resistance in cancer progression. Furthermore, the gene suppression approach was used to identify the role in resistance and resistance reversion.

[KEY FINDINGS] Chemoresistance was associated with actin cytoskeletal reorganization and morphological changes, characterized by a shift from an elongated, filamentous-actin-dominant structure in non-resistant cells to a cobblestone-like morphology with cortical actin in resistant cells, accompanied by a significant reduction in cell surface area. Notably, increased cofilin-2 (CFL2) expression maintained the cortical actin in resistant cells. Suppression of CFL2, prolonged estrogen stimulation, or tamoxifen withdrawal induced a reversal of cortical-to-elongated branched actin, highlighting the dynamic and reversible nature of actin remodeling and cellular plasticity. CFL2 suppression and tamoxifen withdrawal maintained mesenchymal phenotype in resistant cells, while restoring tamoxifen sensitivity and significantly reducing their invasiveness. In contrast, although estrogen stimulation preserved the resistant phenotype, it concurrently attenuated invasiveness. Importantly, tamoxifen and CFL2 expression independently reduced estrogen receptor alpha (ER-α) levels, a characteristic of chemoresistant cells, and were crucial for restoring tamoxifen sensitivity by upregulating ER-α.

[SIGNIFICANCE] These findings underscore the critical roles of CFL2 and tamoxifen in orchestrating actin organization and plasticity, chemoresistance, and indicate potential strategies for reversing therapeutic resistance.