Opposite and dynamic regulation of the interferon response in metastatic and non-metastatic breast cancer

Abstract

Background To our current understanding, solid tumors depend on suppressed local immune reactions, often elicited by the interaction between tumor cells and tumor microenvironment (TME) components. Despite an improved understanding of anti-cancer immune responses in the TME, it is still unclear how immuno-suppressive TME are formed and how some cancer cells survive and metastasize. Methods To identify the major adaptations that cancer cells undergo during tumor development and progression, we compared the transcriptome and proteome from metastatic 66cl4 and non-metastatic 67NR cell lines in culture versus their corresponding mouse mammary primary tumors. Using confocal microscopy, RT-qPCR, flow cytometry and western blotting, we studied the signaling pathway and the mechanisms involved. In addition, we used public gene expression data from human breast cancer biopsies to evaluate the correlation between gene expression and clinical outcomes in patients. Results We found that type I interferon (IFN-I) response was a key differentially regulated pathway between metastatic and non-metastatic cell lines and tumors. The IFN-I response was active in metastatic cancer cells in culture and markedly dampened when these cells formed primary tumors. Interestingly, the opposite was observed in non-metastatic cancer cells and tumors. Consistent with an active IFN-I response in culture, the metastatic cancer cells displayed elevated levels of cytosolic DNA from both mitochondria and ruptured micronuclei with concomitant activation of cGAS-STING signaling. Interestingly, decreased IFN-I-related gene expression in breast cancer biopsies correlated with an unfavourable prognosis in patients. Conclusion Our findings show that IFN-I response is dampened in the tumors with the metastatic ability and lower IFN-I expression predicts poor prognosis in triple-negative and HER2 enriched breast cancer patients. This study highlights the possibility of reactivating the IFN-I response as a potential therapeutic strategy in breast cancer. Graphical abstract

The Regulation and Immune Signature of Retrotransposons in Cancer

“…Therefore, the effect of IFN on retrotransposons could be related to the hormone-regulated microenvironment and might be tumor type-specific. The context-dependent IFN signaling associated with the ER+ and ER-negative breast cancer subtypes, which impacts their response to therapy and overall outcomes, reinforces the above notion [152]. It could be interesting to extend these experiments to identify the levels of retrotransposon expression among ER+ and ERbreast tumors.…”

Identification of modules and key genes associated with breast cancer subtypes through network analysis

“…However, this is the first time that it has been identified as a potential biomarker associated with the Basal A subtype. Recently, Lamsal et al 88 demonstrated that IFIT3 mRNA and its protein are highly expressed in human metastatic breast cancer cell line MDA-MB-231, while its expression is low in non-metastatic MDA-MB-453 cell line. The next hub gene, PSMB9 , encodes a modified enzyme with peptidase activity involved in the proteasome pathway, which helps cells deal with oxidative and proteotoxic stress.…”

NUPR1 packaged in extracellular vesicles promotes murine triple-negative breast cancer in a type 1 interferon-independent manner

“…Studies have demonstrated that IFN1 signaling induces the expression of pro-apoptotic, anti-angiogenic, and immunomodulatory genes that could be used in therapy against cancers and infectious diseases. In randomized trials, administration of IFN1 ligands resulted in the upregulation of estrogen receptors (ERs) in breast cancer tumor cells that would make them sensitive to ER-targeted therapies [26] . However, examination of IFN1 signaling in cancer cells is insufficient to determine breast cancer progression.…”