Long-term exposure to carcinoma-associated fibroblasts makes breast cancer cells addictive to integrin β1.

We studied the long-term effect of stromal factors on the development of fulvestrant-resistance (FR) and fulvestrant-induced dormancy (D). Sublines established from stroma-treated FR-cells (C-FR cells) and D-cells (C-D cells) show permanently high expression of integrin β1 as well as Bcl-3 and P-STAT3 (C-FR) or IGF1R (C-D). Yet, cells fail to withstand fulvestrant better and do not migrate or grow faster than control cells. Instead, C-D cells rely on stromal factors to perform as well as control cells. In addition, C-FR cells adapted to integrin β1 for growth in 3D cultures. These data suggest that long-term exposure to stromal factors leads to addiction rather than better performance in cellular activities. We also found that morphologically distinct breast cancer cell line subpopulations share key responses to stromal factors suggesting that intratumoral heterogeneity may play a minor role in the interaction between breast cancer and stromal cells.