β 2 -Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer

Chronic stress accelerates metastasis - the main cause of death in cancer patients - through the activation of beta -adrenoceptors ( beta ARs). We have previously shown that beta 2AR signaling in MDA-MB-231HM breast cancer cells, facilitates invadopodia formation and invasion in vitro. However, in the tumor microenvironment where many stromal cells also express beta AR, the role of beta 2AR signaling in tumor cells in metastasis is unclear. Therefore, to investigate the contribution of beta 2AR signaling in tumor cells to metastasis in vivo, we used RNA interference to generate MDA-MB-231HM breast cancer cells that are deficient in beta 2AR. beta 2AR knockdown in tumor cells reduced the proportion of cells with a mesenchymal-like morphology and, as expected, reduced tumor cell invasion in vitro. Conversely, overexpression of beta 2AR in low metastatic MCF-7 breast cancer cells induced an invasive phenotype. Importantly, we found that knockdown of beta 2AR in tumor cells significantly reduced the impact of stress on metastasis in vivo. These findings highlight a crucial role for beta 2AR tumor cell signaling in the adverse effects of stress on metastasis, and indicate that it may be necessary to block beta 2AR on tumor cells to fully control metastatic progression.