C/EBPβ, but not C/EBPα, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland

Seagroves, Tiffany N.; Krnacik, Susanne; Raught, Brian; Gay, Jason; Burgess-Beusse, Bonnie; Darlington, Gretchen J.; Rosen, Jeffrey M.

doi:10.1101/gad.12.12.1917

Cited by 235 publications

(217 citation statements)

References 54 publications

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“…Moreover, these transcription factors have been shown to act cooperatively on other promoters such as that of CDllc in myeloid cells (Lopez-Rodriguez et al, 1997) and the placenta-specific trophoblast gene PLAC-1 (Koslowski et al, 2009). C/EBPβ is essential to mouse mammary gland development (Seagroves et al, 1998;Seagroves et al, 2000) as well as other processes such as mouse adipocyte differentiation (Tang and Lane, 1999). C/EBPβ −/− mice display overexpression and disruption of cellular PR expression that coincides with a 10-fold decrease in mammary cell proliferation following steroid stimulation (Seagroves et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP

Goldhar

Duan

Ginsburg

et al. 2011

Molecular and Cellular Endocrinology

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Prolactin (Prl) and progesterone (P) cooperate synergistically during mammary gland development and tumorigenesis. We hypothesized that one mechanism for these effects may be through mutual induction of receptors (R). EpH4 mouse mammary epithelial cells stably transfected with PR-A express elevated levels of PrlR mRNA and protein compared to control EpH4 cells that lack the PR. Likewise, T47D human breast cancer cells treated with P overexpress the PrlR and activate PrlR promoter III. PrlR promoter III does not contain a classical P response element but contains several binding sites for transcription proteins, including C/EBP, Sp1 and AP1, which may also interact with the PR. Using promoter deletion and site directed mutagenesis analyses as well as gel shift assays, cooperative activation of the C/EBP and adjacent Sp1A, but not the Sp1B or AP1, sites by P is shown to confer P responsiveness leading to increased PrlR transcription.

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Section: Discussionmentioning

confidence: 99%

Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP

Goldhar

Duan

Ginsburg

et al. 2011

Molecular and Cellular Endocrinology

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“…A data base search to identify candidate transcription factors that may bind the p53 promoter within the Ϫ972/Ϫ953 region as well as some preliminary DNA-binding assays revealed one factor (C/EBP␤) as a likely candidate. C/EBP␤ is a CCAAT enhancer-binding protein and is critical for normal proliferation and differentiation of mammary epithelial cells (29,30,34,38) as well as numerous other cell types (27,28). It has also been shown to transactivate the c-fos serum response element upon activation of the Ras-dependent signaling pathway in response to mitogenic stimulation (31).…”

Section: Discussionmentioning

confidence: 99%

“…Here we have demonstrated that the transcription factor C/EBP␤ (CAAT/enhancer-binding protein-␤) binds to this regulatory site on the p53 promoter in response to mitogen stimulation and serves to increase p53 promoter expression as cells enter S phase. Because C/EBP␤ is a transcription factor that is critical for normal proliferation and differentiation of a number of cell types (27)(28)(29)(30) and has also been demonstrated to play a role in mitogen-stimulated induction of cell division (31), we have carried out a experiments to establish whether it also has a role in regulating p53.…”

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confidence: 99%

C/EBPβ Participates in Regulating Transcription of the p53 Gene in Response to Mitogen Stimulation

Boggs

Reisman

2007

Journal of Biological Chemistry

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The tightly regulated expression of p53 contributes to genomic stability, and transcription of the p53 gene is induced prior to cells entering S phase, possibly as a mechanism to ensure a rapid p53 response in the event of DNA damage. We have previously described the cloning of an additional 1000 bp of upstream p53 sequences that we have demonstrated play a role in the regulated expression of p53. As described in an earlier report, we preliminarily identified that a member of the CAAT/ enhancer-binding protein (C/EPB) family of transcription factors may play a role in regulating p53. Here we have demonstrated that a particular C/EBP␤ isoform, C/EBP␤-2, efficiently binds to the p53 promoter and induces its expression in a fashion that reflects the pattern of p53 expression seen as cells are induced to enter S phase and is absent from cells that are defective in proper p53 regulation. We conclude from these findings that C/EBP␤-2 plays a central role in the regulating of p53 transcription during the transition into S phase.

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“…Expression of the transgene was assessed by Northern analysis of RNA extracted from adult tissues. Whole-mount analysis of mammary glands taken from virgin mice at various phases of the reproductive cycle was performed as described (Seagroves et al 1998). …”

Section: Generation and Analysis Of Transgenic Animalsmentioning

confidence: 99%

PPARγ signaling exacerbates mammary gland tumor development

Sáez¹,

Rosenfeld²,

Livolsi³

et al. 2004

Genes Dev.

171

148

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Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor ␥ (PPAR␥) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR␥ ligands. To evaluate the therapeutic potential of increased PPAR␥ signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR␥ in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPAR␥ potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPAR␥ signaling serves as a tumor promoter in the mammary gland. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, ligand-responsive transcription factors that participate in many important physiological processes . Mammals have three different PPARs (PPAR␣, PPAR␦, PPAR␥) that form functional heterodimers with the retinoid receptor RXR. These complexes are chief regulators of lipid storage and catabolism. Native and oxidized polyunsaturated fatty acids bind the PPARs and stimulate their transcriptional activity. The function of the PPARs is also modulated by arachidonic acid derivatives, such as prostaglandins and eicosanoids.PPAR␥ is the best-characterized member of the family. Its most prominent role is to regulate differentiation of cell types with active lipid metabolism, such as adipocytes and macrophage foam cells Walczak and Tontonoz 2002). The importance of this receptor in lipid homeostasis and energy balance is accentuated by the widespread use of thiazolidinediones (TZDs), synthetic PPAR␥ ligands, as antidiabetic drugs. The existence of FDA-approved PPAR␥ agonists and the ability of this receptor to induce cellular differentiation encouraged us to explore whether stimulation of PPAR␥ activity could curtail malignant cell growth, in analogy with what is observed with retinoic acid in acute promyelocytic leukemia.A survey of tumors revealed that PPAR␥ is generally overexpressed in liposarcoma, colon, breast, and prostate carcinoma (Tontonoz et al. 1997;DuBois et al. 1998). When treated with PPAR␥ and RXR ligands, cell lines derived from these neoplasms undergo morphological transformation and growth arrest in vitro (Tontonoz et al. 1997;Elstner et al. 1998;Kubota et al. 1998;Mueller et al. 1998;Sarraf et al. 1998). Additional cell culture studies have suggested that lung, pancreatic, and hematopoietic tumor cells also respond to thiazolidinedione treatment (Sporn et al. 2001). These observations prompted trials to evaluate PPAR␥ agonists as therapeutics in human liposarcoma, colon, breast, and prostate cancer...

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C/EBPβ, but not C/EBPα, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland

Cited by 235 publications

References 54 publications

Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP

Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP

C/EBPβ Participates in Regulating Transcription of the p53 Gene in Response to Mitogen Stimulation

PPARγ signaling exacerbates mammary gland tumor development

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