CCAAT/enhancer binding protein beta (C/EBPβ)-2 transforms normal mammary epithelial cells and induces epithelial to mesenchymal transition in culture

Bundy, Linda M.; Sealy, Linda

doi:10.1038/sj.onc.1206216

Cited by 107 publications

(114 citation statements)

References 38 publications

(53 reference statements)

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“…However, untreated levels were unaffected by the addition of ATRA (Figure 5d). C/EBPβ has been attributed a tumor-promoting role in breast and prostate cancer [46][47][48] and shown to be a negative regulator of miR-145, Figure 7 A model for regulation of tumor-suppressor phosphatase, PHLPP2, in AML cells. In unperturbed AML cells, RNA polymerase II binds to and activates the miR-17-92 cluster.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

et al. 2016

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PHLPP2, a member of the PH-domain leucine-rich repeat protein phosphatase (PHLPP) family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little is known, however, regarding its regulation in hematological malignancies. We observed that PHLPP2 protein expression, but not its mRNA, was suppressed in late differentiation stage acute myeloid leukemia (AML) subtypes. MicroRNAs (miR or miRNAs) from the miR-17-92 cluster, oncomir-1, were shown to inhibit PHLPP2 expression and these miRNAs were highly expressed in AML cells that lacked PHLPP2 protein.Studies showed that miR-17-92 cluster regulation was, surprisingly, independent of transcription factors c-MYC and E2F in these cells; instead all-trans-retinoic acid (ATRA), a drug used for terminally differentiating AML subtypes, markedly suppressed miR-17-92 expression and increased PHLPP2 protein levels and phosphatase activity. Finally, we demonstrate that the effect of ATRA on miR-17-92 expression is mediated through its target, transcription factor C/EBPβ, which interacts with the intronic promoter of the miR-17-92 gene to inhibit transactivation of the cluster. These studies reveal a novel mechanism for upregulation of the phosphatase activity of PHLPP2 through C/EBPβ-mediated repression of the miR-17-92 cluster in terminally differentiating myeloid cells. Phosphatases are pivotal components of intracellular signaling cascades, controlling essential processes like metabolism, apoptosis, proliferation and differentiation. 1 The PH-domain leucine-rich repeat protein phosphatase (PHLPP) family serine-threonine phosphatases are emerging as central factors in cell survival and death regulation. The PHLPP2 is a member of this family. 2,3 To date four PHLPP substrates, Akt, PKC, Mst1 and S6K1, have been identified, all kinases involved in cell survival or apoptosis. 4-7 Dephosphorylation inactivates Akt, S6K1 and PKC, and subsequently cell survival signaling, whereas dephosphorylation of Mst1 activates its apoptotic function.PHLPP protein expression and activity is suppressed through various mechanisms in cancers. Although most studies on PHLPP2 have focused on genetic alterations in solid tumors, 8 PHLPP2 protein expression in small cell lung and colorectal cancers is also restricted through translational suppression 9 and post-transcriptional control by microRNAs (miR or miRNAs), miR-205 and miR-224. 10,11 The PHLPP2 3' untranslated region (3'UTR) harbors complementary binding sites for a subset of miRNAs belonging to the miRNA-17-92 cluster. 12 This cluster comprises six miRNAs on chromosome 13, transcribed as a single polycistronic unit. 13,14 Also known as oncomir-1, the cluster enhances cell proliferation or inhibits apoptosis by suppressing targets such as Bim, E2F1 and PTEN and is markedly overexpressed in human cancers. [15][16][17][18][19][20][21] Reduced levels of PHLPP2 in chemoresistant miR-17-92 overexpressing mantle cell lymphomas had suggested that the phosphatase could be a target of oncomir-1. 12 Kno...

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Section: Discussionmentioning

confidence: 99%

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

et al. 2016

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“…These multiple functions, taken together, strongly suggest a crucial role for BMP2 in the pathogenesis of MCB. CCAAT/enhancer binding protein beta (C/EBPbeta), a bZIP transcription factor involved in the regulation of genes involved in immune responses and in the stimulation of expression of the collagen type I gene, induces EMT of mammary epithelia (Bundy and Sealy, 2003). The identification of C/EBPbeta as an MCB-overexpressed gene could indicate a potential role for this transcription factor in the EMT in MCBs.…”

Section: Discussionmentioning

confidence: 99%

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition

Lien

Hsiao

Lin³

et al. 2007

Oncogene

187

156

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Metaplastic carcinoma of the breast (MCB) is a poorly understood subtype of breast cancer. It is generally characterized by the coexistence of ductal carcinomatous and transdifferentiated sarcomatous components, but the underlying molecular alterations, possibly related to epithelial-mesenchymal transition (EMT), remain elusive. We performed transcriptional profiling using half-agenome oligonucleotide microarrays to elucidate genetic profiles of MCBs and their differences to those of ductal carcinoma of breasts (DCBs) using discarded specimens of four MCBs and 34 DCBs. Unsupervised clustering disclosed distinctive expression profiles between MCBs and DCBs. Supervised analysis identified gene signatures discriminating MCBs from DCBs and between MCB subclasses. Notably, many of the discriminator genes were associated with downregulation of epithelial phenotypes and with synthesis, remodeling and adhesion of extracellular matrix, with some of them have known or inferred roles related to EMT. Importantly, several of the discriminator genes were upregulated in a mutant Snail-transfected MCF7 cell known to exhibit features of EMT, thereby indicating a crucial role for EMT in the pathogenesis of MCBs. Finally, the identification of SPARC and vimentin as poor prognostic factors reinforced the role of EMT in cancer progression. These data advance our understanding of MCB and offer clues to the molecular alterations underlying EMT.

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“…The C/EBPb gene expresses three different isoforms by virtue of alternative translation initiation or regulated proteolysis (Ramji and Foka, 2002). Human C/EBPb-2 (comparable to the major form expressed in mouse) expression is increased in breast cancer cell lines and primary breast tumors (Bundy and Sealy, 2003). Moreover, overexpression of C/EBPb-2 in a human mammary epithelial cell line lead to anchorage independence and invasive properties (Bundy and Sealy, 2003).…”

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confidence: 99%

“…Human C/EBPb-2 (comparable to the major form expressed in mouse) expression is increased in breast cancer cell lines and primary breast tumors (Bundy and Sealy, 2003). Moreover, overexpression of C/EBPb-2 in a human mammary epithelial cell line lead to anchorage independence and invasive properties (Bundy and Sealy, 2003). C/EBPb is highly expressed in colorectal tumors (Rask et al, 2000) and is associated with ovarian tumor progression (Sundfeldt et al, 1999).…”

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confidence: 99%

Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

et al. 2005

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The CCAAT/enhancer binding protein b (C/EBPb) is implicated in the regulation of many different molecular and physiological processes. Mice with a germline deletion of C/EBPb (C/EBPb À/À ) display phenotypes in a multitude of cell types and organ systems, including skin where C/EBPb À/À mice exhibit increased apoptosis in epidermal keratinocytes in response to carcinogen treatment and are completely resistant to carcinogen-induced skin tumorigenesis. To determine the contribution of systemic versus cell autonomous functions of C/EBPb to specific phenotypes, mice with a conditional 'floxed' C/EBPb null allele were generated. Epidermal-specific deletion of C/EBPb was achieved by Cre recombinase expression from a keratin 5 (K5) promoter. Similar to C/EBPb À/À mice, K5-Cre;C/ EBPb fl/fl mice were completely refractory to 7,12 dimethylbenz[a]anthracene (DMBA)-induced skin tumorigenesis and these mice displayed increased DMBA-induced apoptosis in epidermal keratinocytes compared to wild-type mice. In contrast, mice lacking the related gene, C/EBPd, were not resistant to DMBA-induced skin tumorigenesis, indicating a unique role of C/EBPb in skin tumor development. Our findings demonstrate that C/EBPb exerts an essential, keratinocyte-intrinsic role in cell survival in response to carcinogen treatment and the elimination of C/EBPb in keratinocytes is sufficient to confer complete resistance of the skin to chemical carcinogenesis.

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CCAAT/enhancer binding protein beta (C/EBPβ)-2 transforms normal mammary epithelial cells and induces epithelial to mesenchymal transition in culture

Cited by 107 publications

References 38 publications

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition

Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

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