The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen -/-mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growthstimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and β-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIα3, a proteolytic product of the fulllength molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.
The peroxisome proliferator-activated receptor ␥ (PPAR␥) is a central regulator of adipogenesis and recruits coactivator proteins in response to ligand. However, the role of another class of nuclear cofactors, the nuclear receptor corepressors, in modulating PPAR␥ transcriptional activity is less clear. Such corepressors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT). Our data suggest that PPAR␥ recruits SMRT and NCoR in the absence of ligand and that these corepressors are capable of down-regulating PPAR␥-mediated transcriptional activity. The addition of the PPAR␥ ligand pioglitazone results in dissociation of the PPAR␥-corepressor complex. To define the role of SMRT and NCoR in PPAR␥ action, 3T3-L1 cells deficient in SMRT or NCoR were generated by RNA interference. When these cells are exposed to differentiation media, they exhibit increased expression of adipocyte-specific genes and increased production of lipid droplets, as compared with control cells. These data suggest that the nuclear receptor corepressors decrease PPAR␥ transcriptional activity and repress the adipogenic program in 3T3-L1 cells. The thyroid hormone receptors (TRs)1 and retinoic acid receptors (RARs) are nuclear receptors that repress gene transcription in the absence of their respective ligands. This ligandindependent repression is mediated by nuclear receptor corepressors, such as the nuclear receptor corepressor protein (NCoR) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT) (1, 2). NCoR and SMRT are recruited by TR and RAR isoforms in the absence of ligand and are released upon ligand binding. NCoR and SMRT, in turn, recruit a complex with histone deacetylase activity to repress transcription of target genes. More recently, NCoR and SMRT have been shown to be recruited by other nuclear receptors, some of which bind nuclear receptor corepressors in the presence of antagonists. However, it has been controversial whether NCoR and SMRT play a significant role in gene regulation by the peroxisome proliferator-activated receptor ␥ (PPAR␥) isoforms (3).Two types of PPAR␥ isoforms exist, PPAR␥1 and PPAR␥2. These receptors differ only in their amino-terminal A/B domain, such that PPAR␥2 contains an extra 30 amino acids (4). The function of PPAR␥2 has attracted considerable interest because it is specifically expressed in adipocytes and is an essential regulator of adipogenesis. In addition, many important adipocyte-specific genes contain response elements for PPAR␥ in their promoter regions. Although PPAR␥ clearly recruits coactivators in response to exogenous ligands, its ability to recruit corepressors is less certain. In contrast to the TR, PPAR␥ does not appear to be a strong repressor in the absence of its ligand. Such experiments, however, have been limited by the lack of information concerning physiologic endogenous ligands. Early work into PPAR␥ and corepressor recruitment suggested that PPAR␥ might not recruit NCoR or SMRT in the p...
Hepatic gluconeogenesis is essential for maintenance of normal blood glucose concentrations and is regulated by opposing stimulatory (cyclic adenosine monophosphate, cAMP) and inhibitory (insulin) signaling pathways. The cAMP signaling pathway leads to phosphorylation of cAMP response element-binding (CREB) protein, resulting in recruitment of the coactivators CREB-binding protein (CBP) and p300 and subsequent activation of gluconeogenesis. Insulin signaling leads to phosphorylation of CBP at serine 436, a residue near its CREB-interacting domain, but it is unknown whether this event modulates cAMP signaling. Here, we show in vitro and in 'knock-in' mice that a mutant CBP (S436A) is aberrantly recruited to CREB protein, resulting in inappropriate activation of gluconeogenesis in the fed state and glucose intolerance resulting from increased hepatic glucose production. We propose that insulin signaling may directly regulate many cAMP signaling pathways at the transcriptional level by controlling CBP recruitment.
Estrogen-nonresponsive estrogen receptor-alpha (ERalpha) knock-in (ENERKI) mice were generated to distinguish between ligand-induced and ligand-independent ER-alpha actions in vivo. These mice have a mutation [glycine 525 to leucine (G525L)] in the ligand-binding domain of ERalpha, which significantly reduces ERalpha interaction with and response to endogenous estrogens, whereas not affecting growth factor activation of ligand-independent pathways. ENERKI mice had hypoplastic uterine tissues and rudimentary mammary gland ductal trees. Females were infertile due to anovulation, and their ovaries contained hemorrhagic cystic follicles because of chronically elevated levels of LH. The ENERKI phenotype confirmed that ligand-induced activation of ERalpha is crucial in the female reproductive tract and mammary gland development. Growth factor treatments induced uterine epithelial proliferation in ovariectomized ENERKI females, directly demonstrating that ERalpha ligand-independent pathways were active. In addition, the synthetic ERalpha selective agonist propyl pyrazole triol (PPT) and ER agonist diethylstilbestrol (DES) were still able to activate ligand-induced G525L ERalpha pathways in vitro. PPT treatments initiated at puberty stimulated ENERKI uterine development, whereas neonatal treatments were needed to restore mammary gland ductal elongation, indicating that neonatal ligand-induced ERalpha activation may prime mammary ducts to become more responsive to estrogens in adult tissues. This is a useful model for in vivo evaluation of ligand-induced ERalpha pathways and temporal patterns of response. DES did not stimulate an ENERKI uterotrophic response. Because ERbeta may modulate ERalpha activation and have an antiproliferative function in the uterus, we hypothesize that ENERKI animals were particularly sensitive to DES-induced inhibition of ERalpha due to up-regulated uterine ERbeta levels.
The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen -/-mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growthstimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and β-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIα3, a proteolytic product of the fulllength molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.
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