Glucocorticoid Receptor Signaling Mediates Resistance to Therapy in Matrix Rigidity-Induced Dormant Brain Metastatic Breast Cancer Spheroids

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in females. Approximately 20-30% of patients with advanced breast cancer develop brain metastasis. Often, brain metastatic breast cancer (BMBC) exhibits a nonproliferative (dormant) phenotype and therapy resistance due to the unfavorable organ microenvironment. However, the mechanisms by which dormant BMBC micrometastases develop resistance to treatment remain unknown. In the current work, we utilized hyaluronic acid (HA) hydrogels to study the relationship between matrix rigidity-induced dormancy and the drug resistance of BMBC spheroids. BMBC spheroids were cultured on soft (∼0.4 kPa) or stiff (∼4.5 kPa) HA hydrogels, known to induce dormant versus proliferative states, and their response to Paclitaxel (PTX) or Lapatinib (LAP) treatment was measured. Spheroids on soft HA hydrogels were resistant to PTX or LAP treatment. Conversely, spheroids on stiff HA hydrogels were responsive to PTX or LAP treatment. Moreover, the resistance to therapy was mediated by glucocorticoid receptor (GR) signaling via serum/glucocorticoid-regulated kinase 1 (SGK-1) and RANBP1 in triple-negative BMBC cells and β-catenin and GSK-3β in human epidermal growth factor receptor 2 positive (HER2+) BMBC cells. Further, SGK1 inhibition alleviated drug resistance and resulted in response to treatment. Overall, this work provides evidence for dormancy associated drug resistance through GR signaling in BMBC spheroids.