Transcription Factor Networks derived from Breast Cancer Stem Cells control the immune response in the Basal subtype

Silveira, Willian A. da; Palma, Patrícia Vianna Bonini; Sicchieri, Renata Danielle; Villacis, Rolando A R; Mandarano, Larissa Raquel Mouro; Oliveira, Tatiane; Antonio, Heriton Mr; Andrade, Jurandyr Moreira de; Muglia, Valdair Francisco; Rogatto, Sílvia Regina; Theillet, Charles; Manoir, Stanislas du; Tiezzi, Daniel Guimarães

doi:10.1038/s41598-017-02761-6

Cited by 29 publications

(23 citation statements)

References 59 publications

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“…We identified genes that were differentially co-expressed between tumors with high and low infiltrating lymphocyte scores-most of these had already been associated with cancer immunity through other studies [170][171][172][173]. Of particular interest were CXCL13, BTLA, IL7R, LAMP3, and LTB as these genes have been linked to the presence of tertiary lymphoid structures (TLS) and high endothelial venules (HEV) within tumors.…”

Section: Resultsmentioning

confidence: 99%

“…High levels of these two antigens have been linked to an overall better prognosis of patients with breast cancer [175,176]. The same is true for BCL11B, IKZF3, and KLRC4, which have very recently been linked to a prognostic immunogenic signature of triple-negative breast cancers [173,177]. Liu et al [177] found that almost all populations of immune cells, immune system pathways, and their genes were enriched in TNBC compared to both normal samples and other breast cancer subtypes.…”

Section: Tumor-infiltrating Lymphocytesmentioning

confidence: 98%

“…This network included miRNAs; miR-103a, miR-136, miR-146a, miR-299, miR-301, miR-346, miR-369, and miR-494 predicted to interact with gene transcripts: ASB2, BCL11B, BTLA, CD3D, CD3G, CXCL13, CXCR5, FAM65B, IKZF3, IL7R, KCNA3, KLRC4, LAMP3, and LTB. This set of genes, which were all upregulated in high-TIL vs low-TIL samples, has all been linked to immune system processes [170][171][172][173]. Genes such as CD3D and CD3G encode T cell surface glycoproteins and are well-known players in anti-tumor immunity [174].…”

Section: Tumor-infiltrating Lymphocytesmentioning

confidence: 99%

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Secreted breast tumor interstitial fluid microRNAs and their target genes are associated with triple-negative breast cancer, tumor grade, and immune infiltration

et al. 2020

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Background: Studies on tumor-secreted microRNAs point to a functional role of these in cellular communication and reprogramming of the tumor microenvironment. Uptake of tumor-secreted microRNAs by neighboring cells may result in the silencing of mRNA targets and, in turn, modulation of the transcriptome. Studying miRNAs externalized from tumors could improve cancer patient diagnosis and disease monitoring and help to pinpoint which miRNA-gene interactions are central for tumor properties such as invasiveness and metastasis. Methods: Using a bioinformatics approach, we analyzed the profiles of secreted tumor and normal interstitial fluid (IF) microRNAs, from women with breast cancer (BC). We carried out differential abundance analysis (DAA), to obtain miRNAs, which were enriched or depleted in IFs, from patients with different clinical traits. Subsequently, miRNA family enrichment analysis was performed to assess whether any families were over-represented in the specific sets. We identified dysregulated genes in tumor tissues from the same cohort of patients and constructed weighted gene co-expression networks, to extract sets of co-expressed genes and co-abundant miRNAs. Lastly, we integrated miRNAs and mRNAs to obtain interaction networks and supported our findings using prediction tools and cancer gene databases.

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Section: Resultsmentioning

confidence: 99%

Section: Tumor-infiltrating Lymphocytesmentioning

confidence: 98%

Section: Tumor-infiltrating Lymphocytesmentioning

confidence: 99%

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Secreted breast tumor interstitial fluid microRNAs and their target genes are associated with triple-negative breast cancer, tumor grade, and immune infiltration

et al. 2020

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“…The CSC populations of many solid tumors are identified by the expression of specific cell surface markers, such as CD44 1 CD24 2 in breast cancer [5]. Additionally, increased aldehyde dehydrogenase (ALDH) activity as measured by the Aldefluor assay is used to identify the CSCs of many tumors, including breast [6,7], colon [8], liver [9], lung [10], prostate [11], glioblastoma [12], melanoma [13], and head and neck [14]. The resistance of CSCs to conventional treatments suggests they may mediate the incomplete response to a Departments of Pathology, b Microbiology and Immunology, c Psychology and Neuroscience, and chemotherapy and radiation, and contribute to recurrence [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Silencing of TAP1 in Aldefluor+ Breast Cancer Stem Cells Contributes to Their Enhanced Immune Evasion

et al. 2018

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Avoiding detection and destruction by immune cells is key for tumor initiation and progression. The important role of cancer stem cells (CSCs) in tumor initiation has been well established, yet their ability to evade immune detection and targeting is only partly understood. To investigate the ability of breast CSCs to evade immune detection, we identified a highly tumorigenic population in a spontaneous murine mammary tumor based on increased aldehyde dehydrogenase activity. We performed tumor growth studies in immunocompetent and immunocompromised mice. In immunocompetent mice, growth of the spontaneous mammary tumor was restricted; however, the Aldefluor population was expanded, suggesting inherent resistance mechanisms. Gene expression analysis of the sorted tumor cells revealed that the Aldefluor tumor cells has decreased expression of transporter associated with antigen processing (TAP) genes and co-stimulatory molecule CD80, which would decrease susceptibility to T cells. Similarly, the Aldefluor population of patient tumors and 4T1 murine mammary cells had decreased expression of TAP and co-stimulatory molecule genes. In contrast, breast CSCs identified by CD44 CD24 do not have decreased expression of these genes, but do have increased expression of C-X-C chemokine receptor type 4. Decitabine treatment and bisulfite pyrosequencing suggests that DNA hypermethylation contributes to decreased TAP gene expression in Aldefluor CSCs. TAP1 knockdown resulted in increased tumor growth of 4T1 cells in immunocompetent mice. Together, this suggests immune evasion mechanisms in breast CSCs are marker specific and epigenetic silencing of TAP1 in Aldefluor breast CSCs contributes to their enhanced survival under immune pressure. Stem Cells 2018;36:641-654.

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“…Breast carcinoma (BC) is the most prevalent cause of cancerrelated mortality in women worldwide (1,2), both in low-and middle-income countries and approximately 1.67 million new cancer cases were diagnosed in 2012 (25% of all cancers) (3). At present, the treatment of breast cancer mainly involves surgery, radiotherapy and chemotherapy; 75% of patients with breast cancer require radiotherapy.…”

Section: Introductionmentioning

confidence: 99%

Deoxycytidine kinase participates in the regulation of radiation-induced autophagy and apoptosis in breast cancer cells

et al. 2018

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Deoxycytidine kinase (dCK) is a rate limiting enzyme critical for the phosphorylation of endogenous deoxynucleosides and for the anti‑tumor activity of many nucleoside analogs. dCK is activated in response to ionizing radiation (IR) and it is required for the G2/M checkpoint induced by IR. However, whether dCK plays a role in radiation-induced autophagy and apoptosis is less clear. In this study, we reported that dCK decreased IR-induced total cell death and apoptosis, and increased IR-induced autophagy in SKBR3 and MDA‑MB‑231 breast cancer cell lines. A molecular switch exists between apoptosis and autophagy. We further demonstrated that serine 74 phosphorylation was required for the regulation of autophagy. In dCK wild‑type (WT) or dCK S74E (mutant) MDA‑MB‑231 cell models, the expression levels of phospho-Akt, phospho-mammalian target of rapamycin (mTOR) and phospho-P70S6K significantly decreased following exposure to IR. Moreover, the ratio of Bcl‑2/Beclin1 (BECN1) significantly decreased in the S74E mutant cells; however, no change was observed in the ratio of Bcl‑2/BAX. Taken together, our findings indicate that phosphorylated and activated dCK inhibits IR-induced total cell death and apoptosis, and promotes IR-induced autophagy through the mTOR pathway and by inhibiting the binding of Bcl‑2 protein to BECN1.

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Transcription Factor Networks derived from Breast Cancer Stem Cells control the immune response in the Basal subtype

Cited by 29 publications

References 59 publications

Secreted breast tumor interstitial fluid microRNAs and their target genes are associated with triple-negative breast cancer, tumor grade, and immune infiltration

Secreted breast tumor interstitial fluid microRNAs and their target genes are associated with triple-negative breast cancer, tumor grade, and immune infiltration

Epigenetic Silencing of TAP1 in Aldefluor+ Breast Cancer Stem Cells Contributes to Their Enhanced Immune Evasion

Deoxycytidine kinase participates in the regulation of radiation-induced autophagy and apoptosis in breast cancer cells

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