In a study published online in Nature Communications, the research group led by Dr. HU Guohong from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences revealed that NR2F1-AS1, a long non-coding RNA, facilitates breast cancer lung metastatic dormancy by regulating NR2F1 and ΔNp63.

Distant vital organs metastasis of breast cancer accounts for most patients’ death. In the process of metastasis, disseminated tumor cells in the distant organs usually fall into a slow proliferation, sustained survival, and therapy-resistant state, which is termed metastatic dormancy. Dormant tumor cells could exist even decades with being undetectable and the capacity of reactivation to form tumor recurrence.

The researchers in the previous studies have noticed that dormant tumor cells retain the new tumor-initiating capacity after a long period of quiescence, which is a decisive feature of cancer stem-like cells (CSCs). However, the current understanding of the relationship between metastatic dormancy and cancer stemness is not consistent.

There are two independent CSC populations in breast cancer, mesenchymal-like CSC (M-BCSC) and epithelial-like CSC (E-BCSC). E-BCSC is more proliferative and tumorigenic than M-BCSC, and M-BCSC tends to be quiescent. It has been found that the inconsistency in the role of CSCs in metastatic dormancy may be explained by the heterogeneity of CSCs.

In this study, the researchers showed that M-BCSC is more easily disseminated to distant organs from primary tumor than E-BCSC, and disseminated E-BCSC in the lung is more likely to form macro-metastases while M-BCSC tends to be quiescent in the lung.

Transcriptomic analysis revealed that long non-coding RNA NR2F1-AS1 was highly expressed in dormant M-BCSC. Functional studies revealed that NR2F1-AS1 enhanced M-BCSC properties by promoting epithelial-mesenchymal transition of tumor cells facilitating the dissemination of tumor cells in primary tumor, and it inhibited E-BCSC properties impairing the reactivation capacity of tumor cells in the lung. Ultimately, NR2F1-AS1 showed a metastatic dormancy-promoting function. Mechanically, NR2F1-AS1 facilitates the contact between PTBP1 and the 5’ UTR of NR2F1, and PTBP1 promotes NR2F1 translation by recruiting ribosomes to the internal ribosome entry site in 5’ UTR of NR2F1.

Furthermore, the researchers found that NR2F1 impairs the properties of E-BCSC and enhances M-BCSC properties by inhibiting the expression of ΔNP63. Analysis of patient-derived tumor samples confirmed that NR2F1-AS1 is correlated with metastatic dormancy and BCSC properties.

This study elucidated the functional role and mechanisms of NR2F1-AS1 in the regulation of breast cancer lung metastatic dormancy and explained the role of CSCs in metastatic dormancy from the perspective of BCSCs heterogeneity. It deepens the understanding of metastatic dormancy.