β2-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 β-adrenoceptors (βARs). We have previously shown that β2AR signaling in MDA-MB-231(HM) breast cancer cells, facilitates invadopodia formation and invasion in vitro. However, in the tumor microenvironment where many stromal cells also express βAR, the role of β2AR signaling in tumor cells in metastasis is unclear. Therefore, to investigate the contribution of β2AR signaling in tumor cells to metastasis in vivo, we used RNA interference to generate MDA-MB-231(HM) breast cancer cells that are deficient in β2AR. β2AR 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 β2AR in low metastatic MCF-7 breast cancer cells induced an invasive phenotype. Importantly, we found that knockdown of β2AR in tumor cells significantly reduced the impact of stress on metastasis in vivo. These findings highlight a crucial role for β2AR tumor cell signaling in the adverse effects of stress on metastasis, and indicate that it may be necessary to block β2AR on tumor cells to fully control metastatic progression.
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Aeson
A
Chang
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Caroline P
CP
Le
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Adam K
AK
Walker
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Sarah J
SJ
Creed
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Cindy K
CK
Pon
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Sabine
S
Albold
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Dominic
D
Carroll
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Michelle L
ML
Halls
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
J Robert
JR
Lane
Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
Bernhard
B
Riedel
School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia.
Davide
D
Ferrari
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Cousins Center for PNI, UCLA Semel Institute, Jonsson Comprehensive Cancer Center, and UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: erica.sloan@monash.edu.
Erica K
EK
Sloan
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism*
D018343:Receptors, Adrenergic, beta-2
Breast cancer; Chronic stress; Invasion; Metastasis; β(2)-Adrenoceptor