ID1 Promotes Breast Cancer Metastasis by S100A9 Regulation

Gumireddy, Kiranmai; Li, An‐Ping; Kossenkov, Andrew V.; Cai, Kathy Q.; Liu, Qin; Yan, Jinchun; Xu, Hua; Showe, Louise C.; Zhang, Lin; Huang, Qihong

doi:10.1158/1541-7786.mcr-14-0049

Cited by 40 publications

(30 citation statements)

References 49 publications

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“…50 However, the mechanism by which ID1 and ID3 induce metastasis is not clearly understood. 53,54 Given the TGF-b signature data presented above, we sought to determine if ID1 and ID3 data alone could be used as an independent biomarker indicative of TGF-b activation in MSL/CL subtype of breast cancer. Using UNC855 dataset, we show that MSL/CL highly express ID1 and ID3 as an independent gene expression signature ( Fig.…”

Section: Tgf-b Signature Is Highly Expressed In Msl/cl Tnbc and Is Asmentioning

confidence: 99%

Metformin attenuates transforming growth factor beta (TGF-β) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer

et al. 2016

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Mesenchymal stem-like/claudin-low (MSL/CL) breast cancers are highly aggressive, express low cell-cell adhesion cluster containing claudins (CLDN3/CLDN4/CLDN7) with enrichment of epithelial-to-mesenchymal transition (EMT), immunomodulatory, and transforming growth factor-β (TGF-β) genes. We examined the biological, molecular and prognostic impact of TGF-β upregulation and/or inhibition using in vivo and in vitro methods. Using publically available breast cancer gene expression databases, we show that upregulation and enrichment of a TGF-β gene signature is most frequent in MSL/CL breast cancers and is associated with a worse outcome. Using several MSL/CL breast cancer cell lines, we show that TGF-β elicits significant increases in cellular proliferation, migration, invasion, and motility, whereas these effects can be abrogated by a specific inhibitor against TGF-β receptor I and the anti-diabetic agent metformin, alone or in combination. Prior reports from our lab show that TNBC is exquisitely sensitive to metformin treatment. Mechanistically, metformin blocks endogenous activation of Smad2 and Smad3 and dampens TGF-β-mediated activation of Smad2, Smad3, and ID1 both at the transcriptional and translational level. We report the use of ID1 and ID3 as clinical surrogate markers, where high expression of these TGF-β target genes was correlated to poor prognosis in claudin-low patients. Given TGF-β's role in tumorigenesis and immunomodulation, blockade of this pathway using direct kinase inhibitors or more broadly acting inhibitors may dampen or abolish pro-carcinogenic and metastatic signaling in patients with MCL/CL TNBC. Metformin therapy (with or without other agents) may be a heretofore unrecognized approach to reduce the oncogenic activities associated with TGF-β mediated oncogenesis.

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Section: Tgf-b Signature Is Highly Expressed In Msl/cl Tnbc and Is Asmentioning

confidence: 99%

Metformin attenuates transforming growth factor beta (TGF-β) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer

et al. 2016

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“…Id1 interacts with TFAP2A to suppress S100A9 expression. Migratory, invasive phenotypes in vitro and metastasis in vivo induced by Id1 expression can be rescued by reestablishment of S100A9 expression [55]. Id1 gene expression was also correlated with EMT-associated genes including, VIM, SNAI1, SNAI2, and TWIST1 [56].…”

Section: Breast Cancermentioning

confidence: 93%

Inhibitor of Differentiation 1 (Id1) in Cancer and Cancer Therapy

Zhao

Gong

et al. 2020

Int. J. Med. Sci.

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The inhibitor of DNA binding (Id) proteins are regulators of cell cycle and cell differentiation. Of all Id family proteins, Id1 is mostly linked to tumorigenesis, cellular senescence as well as cell proliferation and survival. Id1 is a stem cell-like gene more than a classical oncogene. Id1 is overexpressed in numerous types of cancers and exerts its promotion effect to these tumors through different pathways. Briefly, Id1 was found significantly correlated with EMT-related proteins, K-Ras signaling, EGFR signaling, BMP signaling, PI3K/Akt signaling, WNT and SHH signaling, c-Myc signaling, STAT3 signaling, RK1/2 MAPK/Egr1 pathway and TGF-β pathway, etc. Id1 has potent effect on facilitating tumorous angiogenesis and metastasis. Moreover, high expression of Id1 plays a facilitating role in the development of drug resistance, including chemoresistance, radiation resistance and resistance to drugs targeting angiogenesis. However, controversial results were also obtained. Overall, Id1 represent a promising target of anti-tumor therapeutics based on its potent promotion effect to cancer. Numerous drugs were found exerting their anti-tumor function through Id1-related signaling pathways, such as fucoidan, berberine, tetramethylpyrazine, crizotinib, cannabidiol and vinblastine.

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“…Therefore, a positive correlation between ID1 and S100A9, and S100A8/9 would be expected. However, there is some controversy regarding this relation, as it has also been shown that ID1 downregulates S100A9 in breast cancer and promotes formation of metastasis [25]. Here, we aim to further unravel the relation between ID1 and downstream regulators such as S100A8/9 and S100A9, and investigate whether ID1 may, indeed, be centrally involved in the biology of suppressive myeloid cells.…”

Section: Introductionmentioning

confidence: 98%

High expression of ID1 in monocytes is strongly associated with phenotypic and functional MDSC markers in advanced melanoma

Melief

Coaña

Maas

et al. 2020

Cancer Immunol Immunother

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The efficacy of immunotherapies for malignant melanoma is severely hampered by local and systemic immunosuppression mediated by myeloid-derived suppressor cells (MDSC). Inhibitor of differentiation 1 (ID1) is a transcriptional regulator that was shown to be centrally involved in the induction of immunosuppressive properties in myeloid cells in mice, while it was overexpressed in CD11b + cells in the blood of late-stage melanoma patients. Therefore, we comprehensively assessed ID1 expression in PBMC from stage III and IV melanoma patients, and studied ID1 regulation in models for human monocyte differentiation towards monocyte-derived dendritic cells. A highly significant elevation of ID1 was observed in CD33 + CD11b + CD14 + HLA-DR low monocytic MDSC in the blood of melanoma patients compared to their HLA-DR high counterparts, while expression of ID1 correlated positively with established MDSC markers S100A8/9 and iNOS. Moreover, expression of ID1 in monocytes significantly decreased in PBMC samples taken after surgical removal of melanoma metastases, compared to those taken before surgery. Finally, maturation of monocyte-derived DC coincided with a significant downregulation of ID1. Together, these data indicate that increased ID1 expression is strongly associated with expression of phenotypic and immunosuppressive markers of monocytic MDSC, while downregulation is associated with a more immunogenic myeloid phenotype. As such, ID1 may be an additional phenotypic marker for monocytic MDSC. Investigation of ID1 as a pharmacodynamic biomarker or its use as a target for modulating MDSC is warranted.

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ID1 Promotes Breast Cancer Metastasis by S100A9 Regulation

Cited by 40 publications

References 49 publications

Metformin attenuates transforming growth factor beta (TGF-β) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer

Metformin attenuates transforming growth factor beta (TGF-β) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer

Inhibitor of Differentiation 1 (Id1) in Cancer and Cancer Therapy

High expression of ID1 in monocytes is strongly associated with phenotypic and functional MDSC markers in advanced melanoma

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