Abstract
ESE-1/Elf3 and HER2 appear to establish a positive feedback regulatory loop, but the precise role of ESE-1 in HER2+ breast tumorigenesis remains unknown. Analyzing public repositories, we found that luminal B and HER2 subtype patients with high ESE-1 mRNA levels displayed worse relapse free survival. We stably knocked down ESE-1 in HER2+ luminal B BT474 cells and HER2 subtype SKBR3 cells, which resulted in decreased cell proliferation, colony formation, and anchorage-independent growth in vitro. Stable ESE-1 knockdown inhibited HER2-dependent signaling in BT474 cells and inhibited mTOR activation in SKBR3 cells, but reduced Akt signaling in both cell types. Expression of a constitutively-active Myr-Akt partially rescued the anti-proliferative effect of ESE-1 knockdown in both cell lines. Furthermore, ESE-1 knockdown inhibited cyclin D1, resulting in a G1 delay in both cell lines. Finally, ESE-1 knockdown completely inhibited BT474 cell xenograft tumors in NOD/SCID female mice, which correlated with reduced in vitro tumorsphere formation. Taken together, these results reveal the ESE-1 controls transformation via distinct upstream signaling mechanisms in SKBR3 and BT474 cells, which ultimately impinge on Akt and cyclin D1 in both cell types to regulate cell proliferation. Particularly significant is that ESE-1 controls tumorigenesis and is associated with worse clinical outcomes in HER2 breast cancer.