Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape

Bidwell, Bradley N.; Slaney, Clare Y.; Withana, Nimali P.; Forster, Samuel C.; Cao, Yuan; Loi, Sherene; Andrews, Daniel M.; Mikeska, Thomas; Mangan, Niamh E.; Samarajiwa, Shamith A.; Weerd, Nicole A. de; Gould, Jodee; Argani, Pedram; Möller, Andreas; Smyth, Mark J.; Anderson, Robin L.; Hertzog, Paul J.; Parker, Belinda S.

doi:10.1038/nm.2830

Cited by 418 publications

(388 citation statements)

References 63 publications

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“…Cellular morphology was visualized by hemotoxylin and eosin (H&E) staining. IHC detection of epithelial cells was used to confirm the presence of bone metastases with a previously described protocol (7). Briefly, tissues were subjected to heat-induced epitope retrieval (125 C for 3 minutes under pressure) in citrate buffer (10 mmol/L sodium citrate, pH 6) before incubating with a pan anti-cytokeratin antibody (5 mg/mL,…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

“…Tumor cells can use multiple immune-evasive tactics to survive at various metastatic sites (6), including our recent findings that show a requirement for breast tumor cells to suppress their innate type-I IFN pathway to colonize the bone (7). The type-I IFN family was originally characterized as a group of soluble factors produced by almost all cells in the body that were able to confer an antiviral state (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Rautela

Baschuk

Slaney

et al. 2015

Cancer Immunology Research

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Metastatic progression is the major cause of breast cancerrelated mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1 À/À mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1 À/À mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host hematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating natural killer (NK)-cell population. We find that in vivo-stimulated NK cells derived from wild-type, but not Ifnar1 À/À , mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an antimetastatic strategy.

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Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Rautela

Baschuk

Slaney

et al. 2015

Cancer Immunology Research

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“…In certain cases IFN response is essential for tumor therapy with DNA-damaging agents (5); in other cases the expression of an IFN-related DNA-damage signature correlates with a lack of therapeutic response (6). Consistent with these activities, a number of IFN-regulated factors such as STAT1 (7) and the IFN-regulatory factors (IRF) IRF1 (8), IRF7 (9), and IRF8 (10) have been described as critical players in tumor suppression. The IRF1 and IRF8 proteins fit the classical definition of a tumor suppressor, given their loss of expression or mutation in primary human tumors and in animal models of cancer development (11,12).…”

mentioning

confidence: 99%

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Kalakonda¹,

Nallar²,

Jaber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19) is an interferon-retinoid–regulated growth suppressor that inhibits cell growth by targeting the transcription factor STAT3 for inhibition. In primary human tumors GRIM-19 is suppressed or mutated, leading to constitutive STAT3 activity and indicating the tumor-suppressive function of GRIM-19. To understand the in vivo role of Grim-19 in tumor development, we generated a Grim-19 conditional knockout mouse. We found that deletion of even a single Grim-19 allele is sufficient to augment skin tumorigenesis in mice, thus establishing a critical role for Grim-19 as a tumor suppressor. Tumors that developed in the absence of Grim-19 exhibited mitochondrial respiratory chain dysfunction, elevated glycolysis, and Stat3-responsive gene expression.

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“…To our knowledge, TRIM members have been rarely reported in cancer immune escape that is important for cancer development and progression, but some other immune genes are now reported to be involving it. For example, silencing of IRF7 pathways can promote immune escape of breast cancer cells, facilitating bone metastasis 50. Interestingly, silencing of TRIM26 was found in our study to be able to attenuate the expression of IFN‐mediated immune genes including IRF7 and NFKB2 (Figure 5, Figure S6).…”

Section: Discussionmentioning

confidence: 63%

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response

et al. 2018

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The major histocompatibility complex (MHC) is most closely associated with nasopharyngeal carcinoma (NPC), but the complexity of its genome structure has proven challenging for the discovery of causal MHC loci or genes. We conducted a targeted MHC sequencing in 40 Cantonese NPC patients followed by a two‐stage replication in 1065 NPC cases and 2137 controls of Southern Chinese descendent. Quantitative RT‐PCR analysis (qRT‐PCR) was used to detect gene expression status in 108 NPC and 43 noncancerous nasopharyngeal (NP) samples. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to assess the transcription factor binding site. We discovered that a novel SNP rs117565607_A at TRIM26 displayed the strongest association (OR = 1.909, Pcombined = 2.750 × 10−19). We also observed that TRIM26 was significantly downregulated in NPC tissue samples with genotype AA/AT than TT. Immunohistochemistry (IHC) test also found the TRIM26 protein expression in NPC tissue samples with the genotype AA/AT was lower than TT. According to computational prediction, rs117565607 locus was a binding site for the transcription factor Yin Yang 1 (YY1). We observed that the luciferase activity of YY1 which is binding to the A allele of rs117565607 was suppressed. ChIP data showed that YY1 was binding with T not A allele. Significance analysis of microarray suggested that TRIM26 downregulation was related to low immune response in NPC. We have identified a novel gene TRIM26 and a novel SNP rs117565607_A associated with NPC risk by regulating transcriptional process and established a new functional link between TRIM26 downregulation and low immune response in NPC.

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Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape

Cited by 418 publications

References 63 publications

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response

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