Breast tumor cells primed by endoplasmic reticulum stress remodel macrophage phenotype.

In the pathogenesis of breast cancer, tumor-associated macrophages have the capacity to impinge upon clinical outcomes. In light of this, reconciling mechanisms by which macrophages are primed to facilitate tumor growth and progression provide clinically relevant therapeutic targets. Given the recent linkage between activation of the endoplasmic reticulum (ER) stress response and breast cancer progression, we postulated that, similar to other carcinomas, mammary carcinoma cells undergoing ER stress re-program macrophages in order to foster both tumor cell growth and survival, and tumor angiogenesis. To test this, we modeled the interaction between ER-stressed tumor cells and macrophages in the tumor microenvironment by culturing macrophages in the conditioned medium of mammary carcinoma cells undergoing ER stress. In response to these stimuli, macrophages not only invoked a similar stress response but also adopted a pro-inflammatory phenotype. Additionally, macrophages produced the pro-angiogenic molecule, vascular endothelial growth factor (VEGF), thereby establishing the macrophage phenotype invoked by ER-stressed breast cancer cells as being pro-angiogenic. In aggregate, these findings delineate a role for ER stress-dependent cross-talk between breast tumor cells and TAMs as a potential catalyst for tumor cell growth and tumor-associated angiogenesis. Hence, by suggesting that mammary carcinoma cells cope with ER stress by influencing TAM functionality, we have partially elucidated why enhanced tumor progression and angiogenesis accompany the ER stress response in breast cancer.