High Myc expression and transcription activity underlies intra-tumoral heterogeneity in triple-negative breast cancer

Gupta, Nidhi; Jung, Karen; Wu, Chenming; Alshareef, Abdulraheem; Alqahtani, Hind; Damaraju, Sambasivarao; Mackey, John R.; Ghosh, Sunita; Sabri, Siham; Abdulkarim, Bassam; Bigras, Gilbert; Lai, Raymond

doi:10.18632/oncotarget.15891

Cited by 25 publications

(29 citation statements)

References 50 publications

(85 reference statements)

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“…It is well known that there is a higher proportion of MYC DNA amplification and mRNA high expression in TNBC compared to other subtypes [1,8]; however, the impact of MYC DNA amplification and mRNA high expression in TNBC is not fully understood. In our results, we found that MYC mRNA high expression, but not DNA amplification, in TNBCs was associated with worse OS, which is consistent with previous reports showing that high expression of MYC mRNA is associated with worse prognosis in TNBCs [5]. These findings further imply that MYC mRNA expression, but not DNA amplification, represents true activation of the oncogene.…”

Section: Discussionsupporting

confidence: 92%

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High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer

Katsuta

Yan

Terauchi

et al. 2019

IJMS

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DNA abnormalities are used in inclusion criteria of clinical trials for treatments with specific targeted molecules. MYC is one of the most powerful oncogenes and is known to be associated with triple-negative breast cancer (TNBC). Its DNA amplification is often part of the targeted DNA-sequencing panels under the assumption of reflecting upregulated signaling. However, it remains unclear if MYC DNA amplification is a surrogate of its upregulated signaling. Thus, we investigated the difference between MYC DNA amplification and mRNA high expression in TNBCs utilizing publicly available cohorts. MYC DNA amplified tumors were found to have various mRNA expression levels, suggesting that MYC DNA amplification does not always result in elevated MYC mRNA expression. Compared to other subtypes, both MYC DNA amplification and mRNA high expression were more frequent in the TNBCs. MYC mRNA high expression, but not DNA amplification, was significantly associated with worse overall survival in the TNBCs. The TNBCs with MYC mRNA high expression enriched MYC target genes, cell cycle related genes, and WNT/β-catenin gene sets, whereas none of them were enriched in MYC DNA amplified TNBCs. In conclusion, MYC mRNA high expression, but not DNA amplification, reflects not only its upregulated signaling pathway, but also clinical significance in TNBCs.

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Section: Discussionsupporting

confidence: 92%

“…MYC promotes oncogenesis by regulating cell growth and metabolism [4]. MYC is also associated with stem cell features such as chemo-resistance and self-renewal capability [5]. Thus, MYC transcription is strictly regulated by many signaling pathways including WNT/β -catenin, Notch, and TGF-β pathways [1].…”

Section: Introductionmentioning

confidence: 99%

High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer

Katsuta

Yan

Terauchi

et al. 2019

IJMS

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“…For mammosphere assay, cells were seeded and cultured as previously described [ 11 ]. Briefly, cells were trypsinized and passed through a 40 μm cell strainer (BD, Franklin Lakes, NJ, USA) and seeded into ultra-low adherent plates (Corning, NY, USA) in Mammocult media (StemCell Technologies, Vancouver, BC, Canada) as per manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Gupta

Gopal

et al. 2018

Cancers

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We have previously identified a novel phenotypic dichotomy in breast cancer (BC) based on the response to a SRR2 (Sox2 regulatory region 2) reporter, with reporter responsive (RR) cells being more tumorigenic/stem-like than reporter unresponsive (RU) cells. Since the expression level of Sox2 is comparable between the two cell subsets, we hypothesized that post-translational modifications of Sox2 contribute to their differential reporter response and phenotypic differences. By liquid chromatography-mass spectrometry, we found Sox2 to be phosphorylated in RR but not RU cells. Threonine 116 is an important phosphorylation site, since transfection of the T116A mutant into RR cells significantly decreased the SRR2 reporter luciferase activity and the RR-associated phenotype. Oxidative stress-induced conversion of RU into RR cells was accompanied by Sox2 phosphorylation at T116 and increased Sox2-DNA binding. In a cohort of BC, we found significant correlations between the proportion of tumor cells immuno-reactive with anti-phosphorylated Sox2T116 and a high tumor grade (p = 0.006), vascular invasion (p = 0.001) and estrogen receptor expression (p = 0.032). In conclusion, our data suggests that phosphorylation of Sox2T116 contributes to the tumorigenic/stem-like features in RR cells. Detection of phospho-Sox2T116 may be useful in identifying a small subset of tumor cells carrying stem-like/tumorigenic features in BC.

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“…MYC expression promotes BC proliferation and malignancy [ 4 , 16 , 17 ]. MYC–MAX–MAD network is important for regulating cell physiology [ 18 , 19 ]. This network includes transcriptional regulators that form different heterodimers that activate or repress target gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the proteins in this network function as a molecular switch to regulate gene expression. MYC together with its heterodimerisation partner MAX functions as a tumour-promoting transcriptional regulator [ 17 , 19 ]. In contrast, MAD1, a member of this network, functions as a transcriptional repressor and interacts with MAX to deactivate this molecular switch, thus antagonising the MYC–MAX complex that activates this molecular switch [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

AR–PDEF pathway promotes tumour proliferation and upregulates MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative breast cancer

Cao

Xiang

et al. 2018

Mol Cancer

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BackgroundAndrogen receptor (AR) is expressed in 60%~ 70% oestrogen receptor (ER)-negative breast cancer (BC) cases and promotes the growth of this cancer subtype. Expression of prostate-derived Ets factor (PDEF), a transcription factor, is highly restricted to epithelial cells in hormone-regulated tissues. MYC and its negative regulator MAD1 play an important role in BC progression. Previously, we found that PDEF expression is strongly correlated with AR expression. However, the relationship between AR and PDEF and the function of PDEF in ER-negative BC proliferation are unclear.MethodsAR and PDEF expression in ER-negative BC tissues and cell lines was determined by performing immunohistochemistry or western blotting. Protein expression levels and location were analysed by performing western blotting, RT-qPCR and immunofluorescence staining. Co-immunoprecipitation and chromatin immunoprecipitation assays were performed to validate the regulation of AR–PDEF–MAD1–MYC axis. Moreover, the effect of AR and PDEF on BC progression was investigated both in vitro and in vivo.ResultsWe found that PDEF was overexpressed in ER-negative BC tissues and cell lines and appeared to function as an oncogene. PDEF expression levels were strongly correlated with AR expression in ER-negative BC, and PDEF transcription was positively regulated by AR. PDEF upregulated MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative BC. Finally, we found that compared with the inhibition of AR expression alone, simultaneous inhibition of AR and PDEF expression further suppressed tumour proliferation both in vitro and in vivo.ConclusionsOur data highlight the role of the AR–PDEF–MAD1–MYC axis in BC progression and suggest that PDEF can be used as a new clinical therapeutic target for treating ER-negative BC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0883-0) contains supplementary material, which is available to authorized users.

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High Myc expression and transcription activity underlies intra-tumoral heterogeneity in triple-negative breast cancer

Cited by 25 publications

References 50 publications

High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer

High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer

Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

AR–PDEF pathway promotes tumour proliferation and upregulates MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative breast cancer

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