Abstract The atavism theory of cancer proposes that cancer represents a reversion to unicellular behaviors, possibly as a response to stress. In humans, cortisol is the mediator of both physiological and psychosocial stress. While extensive research has examined the role of cortisol in immune function within the context of cancer, studies investigating the impact of cortisol on intratumor heterogeneity are lacking. We investigated the effect of transient and chronic cortisol exposure on measures of cell behavior corresponding to the hallmarks of cancer in the triple-negative breast cancer cell line Hs578t and the fibroblast cell line BJ-5ta. We hypothesize that long-term exposure to steady-state, physiological levels of cortisol (10 µg/dL) leads to an increase in cellular heterogeneity in both normal and cancerous cells. We grew cells in normal media (control), in the presence of cortisol for at least 4 weeks (selected), or in cortisol for 4 weeks and then returned to normal media (reverted). We observed that cortisol exposure altered multiple cell phenotypes in a cell line-specific manner, with variable effects on intercellular heterogeneity. For example, plating efficiency, a measure of stemness, showed differences in both variability and mean plating efficiency across all three conditions for Hs578t and BJ-5ta. Relative to the control, Hs578t showed an increase in variability in plating efficiency in selected cells that remained in reverted cells. In contrast, only reverted cells demonstrated an increase in mean plating efficiency. BJ-5ta demonstrated an increase in median plating efficiency, accompanied by a reduction in variability, following cortisol exposure, regardless of the timing of exposure. Similarly, when examining the response to paclitaxel or 5-fluorouracil (5-FU), both selected and reverted Hs578t cells were more resistant to both drugs compared to the controls. However, the BJ-5ta response was dependent on the drug. Selected cells were more sensitive to both paclitaxel and 5-FU, while reverted cells demonstrated no difference in sensitivity to paclitaxel, but were more sensitive to 5-FU. Finally, single-cell gene expression analysis of the Hs578t lines revealed a persistent change in gene expression in response to cortisol. Taken together, our results suggest that cortisol exposure produces stable, cell line-specific adaptations and alterations to intercellular variability, highlighting its potential to influence long-term cancer cell behavior and therapeutic response. Citation Format: Cassidy Kennedy, Jackson White, Thuy-Vi Tran, Isabella Bucciferro, Kasey Pull, Brikena Gusek, Kimberly J. Bussey. Physiological concentrations of cortisol induce changes to intercellular heterogeneity in both cancerous and normal cells abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85 (23Suppl): Abstract nr B007.
Kennedy et al. (Thu,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: