Breast cancer dormancy is associated with a 4NG1 state and not senescence

Abstract

Reactivation of dormant cancer cells can lead to cancer relapse, metastasis and patient death. Dormancy is a non-proliferative state and is linked to late relapse and death. No targeted therapy is currently available to eliminate dormant cells, highlighting the need for a deeper understanding and reliable models. Here, we thoroughly characterize the dormant D2.OR and proliferative D2A1 breast cancer cell line models in vivo and in vitro, and assess if there is overlap between a dormant and a senescent phenotype. We show that D2.OR but not D2A1 cells become dormant in the liver of an immunocompetent model. In vitro, we show that D2.OR cells are polyploid ER+/Her2+ cells, and in response to a 3D environment are growth arrested in G1, of which a subpopulation resides in a 4NG1 state. The dormancy state is reversible, and not associated with a senescence phenotype. This will aid future research on breast cancer dormancy.

B3GALT6 Promotes Dormant Breast Cancer Cell Survival and Recurrence by Enabling Heparan Sulfate-Mediated FGF Signaling

“…We next asked whether B3GALT6 might also play a functional role in microenvironment-induced dormancy. To address this question we used the D2.OR-D2A1 system of paired cell lines that share a common origin and grow comparably in two-dimensional (2D) culture, but manifest divergent growth properties (i.e., D2.OR: dormant/indolent vs. D2A1: proliferative/aggressive) when cultured in 3D or at metastatic sites in vivo 16,20,48 .…”

“…We first determined whether a previously derived dormancy-associated gene expression signature generated by comparing D2.OR to D2A1 cells grown in 3D culture 48 This enrichment was reversible following doxycycline readdition, which reactivates Her2 signaling and induces dormant tumor cells to re-enter the cell cycle (Fig. 5A).…”