Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPβ

Gustafson, Tanya L.; Wellberg, Elizabeth A.; Laffin, Brian; Schilling, Lauren; Metz, Richard P.; Zahnow, Cynthia A.; Porter, Weston W.

doi:10.1038/onc.2008.497

Cited by 29 publications

(31 citation statements)

References 37 publications

(49 reference statements)

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“…Furthermore, reestablishment of Sim2s in highly invasive cancer cells significantly inhibits growth and motility, suggesting that Sim2s is a breast tumor suppressor (Kwak et al, 2007). In addition, we found that SIM2s expression is suppressed by NOTCH and CEBPb and that loss of SIM2s in normal human breast and mouse mammary epithelium induces an invasive basal/stem cell-like phenotype (Gustafson et al, 2009;Laffin et al, 2008). Sim2s-null mouse mammary glands do not undergo proper ductal elongation or luminal differentiation (Laffin et al, 2008).…”

Section: Introductionmentioning

confidence: 63%

“…We have previously shown that SIM2s is expressed in human breast luminal epithelial cells and loss of SIM2s in normal human breast cell lines and mouse mammary epithelium during virgin development induces an invasive basal/stem cell-like phenotype (Laffin et al, 2008;Gustafson et al, 2009). To further evaluate the role of Sim2s in mammary gland development, we provide new data demonstrating that Sim2s is upregulated in a stepwise manner during early lactation, similar to that of Csn2 and Wap, but not Lalba and Expi.…”

Section: Discussionmentioning

confidence: 90%

“…With increasing evidence that breast cancer progression correlates with decreased differentiation and induction of an invasive basal/stem cell-like phenotype (Contesso et al, 1987;Kouros-Mehr et al, 2008;Liu et al, 2007), deciphering signals controlling normal mammary gland development and differentiation will provide much needed insight into treating this disease. As we have shown that loss of Sim2s leads to a basal/stem cell-like phenotype and overexpression promotes differentiation (Laffin et al, 2008;Gustafson et al, 2009), we hypothesize that re-establishing SIM2s expression in highly aggressive human breast cancers will promote tumor cell differentiation and block breast cancer progression and metastasis. RESEARCH ARTICLE Sim2s promotes mammary differentiation …”

Section: Research Articlementioning

confidence: 99%

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The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation

et al. 2010

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SUMMARYWe have previously demonstrated that the bHLH/PAS transcription factor, singleminded 2s (Sim2s), is required for proper mammary ductal morphogenesis and luminal epithelial differentiation. Furthermore, loss of Sim2s in breast cancer cells resulted in downregulation of epithelial markers and acquisition of a basal-like phenotype. The objective of this study was to further define the role of Sim2s in mammary differentiation. We found that Sim2s is developmentally regulated throughout mammary gland development with highest expression during lactation. Mammary glands from nulliparous mice expressing Sim2s driven by the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) promoter were morphologically indistinguishable from wild-type mice but displayed hallmarks of precocious lactogenic differentiation. These included elevated expression of the milk protein genes Wap and Csn2, and apical localization of the lactation marker Npt2b. Consistent with the in vivo results, Sim2s enhanced prolactinmediated Csn2 expression in HC11 and CIT3 mouse mammary epithelial cells, and downregulation of Sim2s by shRNA in HC11 cells inhibited Csn2 expression. Chromatin immunoprecipitation (ChIP) analyses of the Csn2 gene found that Sim2s associates with the Csn2 promoter and re-ChIP experiments showed that Sim2s interacted with the RNA II polymerase (RNAPII) complex. Together, these data demonstrate, for the first time, that Sim2s is required for establishing and maintaining mammary gland differentiation.

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Section: Introductionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 90%

Section: Research Articlementioning

confidence: 99%

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The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation

et al. 2010

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“…Zhu et al demonstrated that C/EBPβ-null mice are completely refractory to skin tumor formation induced by a variety of carcinogens which produce tumors containing oncogenic Ras mutations, and that C/EBPβ participated in Ras-induced transformation of NIH 3T3 fibroblasts (16). In Ras-transformed MCF10A cells, C/EBPβ suppressed expression of tumor suppressor Sigleminded-2, which has been found to inhibit malignant transformation of mammary ductal cells (19). Thus, C/ EBPβ is downstream of the Ras signaling pathway and is required for Ras-induced malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

“…C/EBPβ belongs to a basic-leucine zipper transcription factor family and plays multiple roles in the control of inflammation, cellular proliferation, survival and differentiation, and tumorigenesis (14)(15)(16)(17). Recent evidence indicates that C/EBPβ is critical for carcinogen-and oncogene-mediated cell transformation (18,19). Furthermore, C/EBPβ activation is indispensable to liver proliferation and fibrosis (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: Involvement of CCAAT/enhancer binding proteinï¿½β and cyclooxygenase-2

Ren

et al. 2011

Mol Med Report

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Abstract. Cyclooxygenase-2 (COX-2) and CCAAT/enhancer binding protein β (C/EBPβ) have been shown to be involved in inflammation and carcinogenesis, and our previous study revealed that they were co-overexpressed in human hepatocellular carcinoma (HCC) tissue and a positive correlation was found. Saikosaponin-d (SSD), a triterpene saponin extracted from Bupleurum falcatum L. (Umbelliferae), is known to exert inhibitory effects on COX-2 expression, together with inflammation and hepatic fibrosis. These findings prompted us to investigate the chemopreventive potential of SSD against hepatocarcinogenesis and its possible molecular mechanism in vivo. An experimental model with diethylinitrosamine (DEN)-treated Sprague Dawley rats was used in the present study. DEN (50 mg/kg body weight) and SSD (2 mg/kg body weight) were intraperitoneally injected weekly and daily, respectively. Administration of SSD alone had no side effects. The liver nodule formation, tumorous invasion to surrounding organs and increased cellular atypia induced by DEN were markedly reduced by SSD in the SSD + DEN group compared with the DEN group. On the other hand, immunohistochemical staining demonstrated that the expression of COX-2 and C/ EBPβ proteins was significantly increased in tumor cells and macrophages of liver tissue from DEN-treated rats, whereas the expression of the two proteins was markedly lowered in the SSD + DEN group. Overall, our results suggest that SSD prevents DEN-induced hepatocarcinogenesis in rats through inhibition of C/EBPβ and COX-2, providing indispensable experimental evidence for the clinical application of SSD as a novel chemopreventive agent against HCC in the future.

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Promotion of invasion by mutant RAS is dependent on activation of the WASF3 metastasis promoter gene

Teng

Ngoka

Cowell

2017

Genes Chromosomes & Cancer

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Metastasis represents an end stage in the evolution of cancer progression and has been related to specific genetic pathways. Overexpression of mutant RAS in particular appears to promote invasion and metastasis, although exactly how this occurs has not been well characterized. We have previously shown that activation of the WASF3 protein regulates actin cytoskeleton dynamics that promote invasion. In this report we investigated how WASF3 overexpression interacts with mutant RAS to increased invasion and metastasis. The ability of RAS to promote invasion and metastasis was shown to be dependent on WASF3 activation in a PI3K and AKT dependent manner. Proteomics analysis demonstrates the presence of AKT in the WASF3 immunocomplex which is enhanced by overexpression of mutant RAS. During these processes activation of ERK1/2 is not affected by loss of WASF3 expression. Analysis of the relative involvement of p85 and p110 in the WASF3 complex demonstrates that mutant RAS promotes dissociation of p85 promoting activation of p110. These studies provide a deeper understanding of the critical role for WASF3 in facilitating increased invasion potential in cancer cells expressing mutant RAS and supports the idea that targeting WASF3 in metastatic cells overexpressing RAS may be used to suppress invasion and metastasis.

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Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPβ

Cited by 29 publications

References 37 publications

The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation

The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation

Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: Involvement of CCAAT/enhancer binding proteinï¿½β and cyclooxygenase-2

Promotion of invasion by mutant RAS is dependent on activation of the WASF3 metastasis promoter gene

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