Inducible lncRNA transgenic mice reveal continual role of in promoting breast cancer metastasis.

is a 2.2-kb long noncoding RNA (lncRNA) whose dysregulation has been linked to oncogenesis, defects in pattern formation during early development, and irregularities during the process of epithelial-to-mesenchymal transition (EMT). However, the oncogenic transformation determined by in vivo and its impact on chromatin dynamics are incompletely understood. Here, we generate a transgenic mouse model with doxycycline-inducible expression of human in the context of the MMTV-PyMT breast cancer-prone background to systematically interrogate the cellular mechanisms by which human lncRNA acts to promote breast cancer progression. We show that sustained high levels of over time increased breast metastatic capacity and invasiveness in breast cancer cells, promoting migration and subsequent metastasis to the lung. Subsequent withdrawal of overexpression reverted the metastatic phenotype, indicating oncogenic lncRNA addiction. Furthermore, overexpression altered both the cellular transcriptome and chromatin accessibility landscape of multiple metastasis-associated genes and promoted EMT. These alterations are abrogated within several cell cycles after expression is reverted to basal levels, indicating an erasable lncRNA-associated epigenetic memory. These results suggest that a continual role for in programming a metastatic gene regulatory program. Targeting lncRNA may potentially serve as a therapeutic strategy to ameliorate breast cancer progression.