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Query: UNIPROT:P06889 (Mol)
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Morphologically atypical cells were first detected in the adjacent connective tissue 98 days after implanting a paraffin pill containing 2 mg of 7,12-dimethylbenz[a]anthracene (DMBA) into the subcutaneous tissues of rats. These cells subsequently formed groups and finally produced gross malignant fibrous histiocytomas (MFH). Early atypical cells were located between proliferating fibroblasts and histiocytes in the center of a fibrous capsule surrounding the DMBA pill. They exhibited a smooth cell surface, dilated rough endoplasmic reticulum, multiple Golgi complexes, and were often associated with newly formed collagen. These cells incorporated [3H]thymidine and [3H]proline intensively, and showed weak acid phosphatase activity but no features diagnostic of macrophages (microvilli, numerous lysosomes, high acid phosphatase and non-specific esterase activities, antigens recognized by monoclonal antibodies ED1 and OX-42 and vital staining with trypan blue). There was no evidence that atypical cells differentiated into muscle cells (no expression of desmin or the alpha-sarcomeric form of actin) or Schwann cells (no expression of S-100 protein). No point mutation in the neu gene at nucleotide 2007, specific for N-ethyl-N-nitrosourea- and DMBA-induced malignant rat schwannomas, was detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analyses. These results support the view that malignant fibrous histiocytoma is derived from immature fibroblasts exhibiting pronounced phenotypic diversity during the later stages of carcinogenesis.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Development of malignant fibrous histiocytoma induced by 7,12-dimethylbenz[a]anthracene in the rat: characterization of early atypical cells. 790 72

By analysis of skin tumors from F1 hybrid mice we demonstrated that the genetic events that occur during tumor progression depend on the type of chemical carcinogenesis protocol used to induce tumor growth. More than 95% of tumors induced by initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) exhibited mutations in Ha-ras and trisomy of chromosome 7. Carcinomas induced with multiple DMBA treatments had a lower frequency of alterations on chromosome 7 (50%), but only in tumors with Ha-ras mutations, and had a much wider spectrum of alterations, including trisomy, mitotic recombination, deletion, and gene duplication. Carcinomas induced with multiple N-methyl-N'-nitro-N-nitrosoguanidine treatments only rarely exhibited alterations on chromosome 7 (8%), even if they contained mutant Ha-ras. More frequent numerical alterations of chromosome 11 were also seen in TPA-promoted tumors (23%) than in tumors induced by multiple carcinogen treatments (8%). These results show that postinitiation events are nonrandom and fit a model in which promoting agents induce numerical chromosomal alterations but in which mutagens cause more directed mutational events.
Mol Carcinog 1994 Oct
PMID:Induction of different genetic changes by different classes of chemical carcinogens during progression of mouse skin tumors. 791 97

Mice with skin tumors induced either by 7,12-dimethylbenz[a]anthracene complete carcinogenesis or subcutaneous injection of a carcinogenic keratinocyte cell line showed moderate to severe splenomegaly as a result of an increase in splenic granulocyte-macrophage and erythroid (erythroid burst-forming unit) progenitors. To test whether the observed alterations involve the release of soluble factors by the epidermal component of skin tumors, we used an in vitro approach. A series of mouse keratinocyte cell lines resembling progressive stages of skin carcinogenesis and carrying either normal or activated Ha-ras genes were assayed for their ability to produce the factors required for colony growth of hematopoietic-committed progenitors. Only the conditioned media of keratinocytes harboring activated Ha-ras genes were able to support the growth of granulocyte-macrophage colony-forming units. In addition, preincubation of normal bone-marrow cells with conditioned media from the transformed epidermal cell lines stimulated in vitro amplification of the hematopoietic granulocyte-macrophage progenitor compartment. To identify the possible factors responsible for the activities detected in the keratinocyte-conditioned media, we performed northern blot analysis using the cytokine probes granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, stem cell factor, interleukin-1 alpha, interleukin-3, and tumor necrosis factor-alpha. The cell lines expressed different cytokine mRNA combinations that positively correlated with the colony-stimulating activity detected in the corresponding conditioned medium. These results suggest that transformed epidermal tumor cells in vivo may alter normal hematopoiesis as a consequence of the production of cytokines that act in autocrine or paracrine loops probably related to tumor growth.
Mol Carcinog 1994 Nov
PMID:Augmented expression of cytokines in mouse epidermal tumor cells and its possible involvement in the induction of hematopoietic alterations. 794 4

TG.AC mice (which carry a v-Ha-ras transgene) rapidly develop papillomas in response to 12-O-tetradecanoylphorbol-13-acetate (TPA). Approximately 30% of the papillomas are associated with subsequent development of malignancies. Early-passage spindle-shaped tumor cells arising from explant cultures of TPA-induced tumors in TG.AC mice were tumorigenic when transplanted to syngeneic recipients. The v-Ha-ras transgene in the transplanted tumors was expressed at a high level. To identify possible genetic changes associated with the development of malignant tumors, explanted cells were cultured in vitro and assessed for karyotypic changes between the second and third passages by analyzing G-banded metaphase chromosomes. For comparison, skin malignancies were induced in nontransgenic FVB/N mice (parent strain) by 7,12-dimethylbenz[a]anthracene (DMBA) initiation and TPA promotion, and their G-banded metaphase chromosomes were analyzed. Trisomy (in at least 50% of about 30 metaphases) of chromosome 15 (in five of 15 tumors) and chromosome 6 (four of 15 tumors) was observed in TG.AC mice, independent of chemical treatment or tumor type. Of six tumors from DMBA/TPA-treated FVB/N mice, three had trisomy 10 or 15 (or both), and two appeared normal. The absence of trisomy 7 is notable because c-Ha-ras maps to that chromosome. The absence of trisomy 7 in the six FVB/N DMBA/TPA-induced skin malignancies contrasts with DMBA/TPA-induced karyotypic effects in SENCAR mice. Expression of the v-Ha-ras transgene may have precluded the requirement for endogenous mutant ras and allelic imbalance involving chromosome 7 in TG.AC mice, but it could not have in FVB/N mice. These results suggest the possibility that the observed trisomies are consequential, rather than causal, events in the development of TG.AC or FVB/N skin malignancies. Molecular genetic analysis will be required to understand the changes associated with tumorigenesis in this transgenic line as well as in the parent mouse line.
Mol Carcinog 1994 Dec
PMID:Cytogenetic analysis of malignant skin tumors induced in chemically treated TG-AC transgenic mice. 799 63

The major cytochrome P450 (P450EF) in the mouse embryo fibroblast C3H/10T1/2CL8 (10T1/2) cell line, which is very active in polycyclic aromatic hydrocarbon metabolism, is immunologically distinct from known P450 families but shares homology with an adrenocorticotropin hormone-regulated P450 from rat adrenal glands (P450RAP). P450EF is more effectively induced by benz[a]anthracene (BA) than by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is anomalous for aryl hydrocarbon receptor (AhR)-mediated transcriptional activation. Evidence is presented here that induction of P450EF is consistent with mediation by the AhR but also involves an additional selective stabilization of P450EF by BA. P450EF-specific mRNA was measured by in vitro translation of 10T1/2 mRNA and subsequent immunoprecipitation with antibodies that recognize P450EF. P450EF mRNA was equally stimulated (> 10-fold) by BA (10 microM) and TCDD (10 nM) after 6 hr of induction in 10T1/2 cells. This equal stimulation of P450EF by BA and TCDD is consistent with transcriptional activation of the gene by the AhR. BA induction of mRNA declined 3-fold between 6 and 18 hr, due to metabolism of BA. Steady state P450EF mRNA levels declined quickly once this stimulation was removed, whereas total P450EF protein levels, measured by immunoblotting, continued to increase. During a 6-hr inhibition of protein synthesis with cycloheximide, both total P450EF and functional cytochrome, measured by polycyclic aromatic hydrocarbon metabolism, decreased by 60% in uninduced and TCDD-induced transformed 10T1/2 cells. This is consistent with relatively rapid degradation of P450EF (t1/2 = 4 hr). No such decline was seen when BA was present, indicating a stabilization of P450EF, which can explain the additional effectiveness of BA in enhancing the level of P450EF.
Mol Pharmacol 1994 Jun
PMID:Dual regulation of cytochrome P450EF expression via the aryl hydrocarbon receptor and protein stabilization in C3H/10T1/2 cells. 802 8

Sex steroids, in particular estradiol (E2) and progesterone (P4), play, together with other hormones and growth factors, a role in the development of normal breast tissue. The effect of four progestagens (norethisterone, 3-ketodesogestrel, gestodene and P4) and Org OD14, a steroid with weak estrogenic, progestagenic and androgenic properties were studied on growth of breast tumor cells in vitro using two subclones of MCF-7 (H and A) and T47D (S and A) cells. In addition, we investigated the effects of 3-ketodesogestrel, gestodene and Org OD14 on the growth of 7,12-dimethylbenz(a)anthracene(DMBA)-induced mammary tumors in rats. In the in vitro assays with MCF-7 cells norethisterone, 3-ketodesogestrel and gestodene stimulated growth only at high doses (> or = 10(-7) M), whereas P4 had no effect. Gestodene was more potent than 3-ketodesogestrel and norethisterone. Org OD14, stimulated cell growth at a dose of 10(-8) M, while E2 is active at 10(-10) M. In T47D-A cells similar effects were found, but the subclone S did not respond to the progestagens and Org OD14. The two T47D subclones also reacted differently to progestagens during growth stimulation with E2. In T47D-S the progestagens and Org OD14 inhibited, while in T47D-A these compounds did not modulate the effect of E2. In the DMBA model we found that gestodene and 3-ketodesogestrel were able to inhibit tumor growth to the same extent. Surprisingly, Org OD14 was even more effective in the DMBA model using the therapeutic approach. Using the prophylaxic approach tumor development was delayed and tumor growth was strongly suppressed. The inhibitory effects of Org OD14 on tumor growth in the DMBA model may be attributed to its mixed hormonal profile. From these studies we conclude that different cell lines and even subclones thereof respond quite differently to steroids. Both in vitro and in vivo studies are required to judge whether synthetic steroids might be involved in an increased risk for the development of breast tumors.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Effects of progestagens and Org OD14 in in vitro and in vivo tumor models. 804 94

We conducted experiments to determine if p53 alterations, which are frequent in human breast cancers, were also common in murine mammary tumors. In 13 mammary tumors from 7,12-dimethylbenz[a]anthracene (DMBA)-treated BALB/c mice were immunohistochemically analyzed for overexpression of p53; p53 protein was not detectable. Three of the tumors were established as cell lines in vitro. p53 protein was rarely detected at passage 4 in these lines but was overexpressed by passage 8 in two of them. The p53 nucleotide sequence was shown to be wild type in one primary mammary tumor and in the two p53-overexpressing cell lines. One cell line that overexpressed p53 in vitro was implanted into BALB/c mice. The resulting tumors retained the wild-type p53 nucleotide sequence but no longer expressed detectable levels of p53 protein, suggesting that the overexpression of wild-type p53 was related to in vitro culture conditions. The effect of DMBA on mammary-tumor development was also tested in mice rendered hemizygous for p53. These mice and wild-type littermate controls had no differences in susceptibility to induction of mammary tumors by oral administration of DMBA. Furthermore, Southern blot hybridization detected no gross alterations in the wild-type p53 allele in mammary tumors from the p53-deficient mice. Point mutation of the wild-type p53 allele was also infrequent in the DMBA-induced mammary tumors from hemizygous p53 mice; it occurred in only one of seven tumors. Thus, the p53 gene is apparently not a primary target for genetic alterations in DMBA-induced mammary tumors. Next, we examined mammary tumors derived from D1 and D2 transplantable hyperplastic alveolar nodule (HAN) outgrowths, which rapidly form tumors containing Ha-ras mutations after DMBA treatment. As ras and p53 mutants can cooperate in transformation, we examined whether D1 and D2 HAN outgrowths have p53 mutations. Unlike in the DMBA-induced primary mammary tumors, nuclear p53 accumulation was observed frequently (10 of 14) in tumors that arose from D1 and D2 HAN outgrowths. Direct sequencing of the entire coding region of the p53 cDNA from six D1 and D2 tumors confirmed that the sequence was wild type. Although wild-type p53 was retained in both DMBA-induced mammary tumors and mammary tumors derived from D1 and D2 preneoplastic outgrowths, wild-type p53 overexpression was detected only in D1 and D2 tumors. Therefore, D1 and D2 tumors appear to arise by a pathway in which p53 expression is altered, whereas DMBA induction affects a different pathway that does not require such alteration.
Mol Carcinog 1994 Mar
PMID:Infrequent p53 mutations in 7,12-dimethylbenz[a]anthracene-induced mammary tumors in BALB/c and p53 hemizygous mice. 814 19

Cultured murine hepatoma 1c1c7 cells were treated with either the actin filament-disrupting drug cytochalasin D or the microtubule inhibitors colchicine and nocadazole (NOC) to assess the role of the cytoskeleton in the process of cytochrome P450 Cyp1a-1 induction. Indirect fluorescence analyses demonstrated that microtubule or actin networks were disrupted within 1 hr of treatment and remained altered as long as cultures were maintained in the presence of the drugs. Treatment of cultures with cytochalasin D, colchicine, or NOC for 1 hr before the addition of dibenz[a,c]anthracene had no effect of Cyp1a-1 induction, as monitored by measurements of CYP1A1 mRNA. Pretreatment with NOC for > or = 18 hr produced populations of cells that had either a flat or rounded morphology. Both populations, when isolated 20-24 hr after NOC treatment, were arrested in the G2/M phase of the cell cycle (83-98% in G2/M versus approximately 7-10% in nontreated or solvent-treated cultures). Cyp1a-1 induction was suppressed in both of these populations, as monitored by measurement of CYP1A1 mRNA content (reductions of > 68%), 7-ethoxyresorufin O-deethylase activity (reductions of > 80%), or microsomal CYP1A1 protein content (reductions of > 80%). In contrast, overall [3H]leucine incorporation into protein was not affected. Cytosol prepared from these NOC-treated cultures bound approximately 39% of the radiolabeled 2,3,7,8-tetrachlorodibenzo-p-dioxin bound by cytosol isolated from solvent-treated cultures. Nuclear extracts prepared from cultures treated with NOC for 20-24 hr before in vivo exposure to inducer and cytoplasmic extracts isolated from similarly NOC-treated cultures that were exposed to inducer in vitro demonstrated reductions of > or = 54% and > or = 55%, respectively, in their abilities to bind to DNA, when analyzed by gel retardation analyses using an oligonucleotide corresponding to dioxin-responsive element D of the Cyp1a-1 gene. These studies suggest that ligand-dependent induction of Cyp1a-1 transcription is unaffected by short term disruption of the microfilament or microtubule network. However, long term exposure to microtubule inhibitors causes cells to pause in the G2/M stage of the cell cycle and modulates processes involved in the induction of Cyp1a-1 in these cells.
Mol Pharmacol 1994 May
PMID:Short and long term effects of cytoskeleton-disrupting drugs on cytochrome P450 Cyp1a-1 induction in murine hepatoma 1c1c7 cells: suppression by the microtubule inhibitor nocodazole. 819 Jan 10

This study was designed to examine the mutagenic specificity of (+)anti-dibenz[a,j]anthracene 3,4-diol-1,2-epoxide ((+)anti-DB[a,j]A-DE) in SOS-induced repair-proficient Escherichia coli ES87 (delta pro-lac, strA)/F' (pro+, lac1Q, lac1am26, lacZ delta M15). The plasmid pUB3, which contains the mutation target gene, supF, was modified with (+)anti-DB[a,j]A-DE in vitro (two to five adducts/plasmid) and then transformed into bacteria by electroporation. The spontaneous mutation frequency for unmodified pUB3 in uninduced cells was about 2 x 10(-6) and for SOS-induced cells, about 8 x 10(-6). The spontaneous supF- mutations were primarily insertions, deletions, and frameshifts. The mutation frequency for (+)anti-DB[a,j]A-DE-modified pUB3 was about 8 x 10(-6) and about 32 x 10(-6) for uninduced cells and SOS-induced cells, respectively. (+)anti-DB[a,j]A-DE induced primarily point mutations in supF in SOS-induced cells. GC-->AT transitions were the major mutations observed in SOS-induced cells (37%). GC-->TA (21%) and GC-->CG (8.6%) transversion mutations were also observed, whereas mutations at AT base pairs were rare (1.9%). Furthermore, a large number of tandem GC/GC-->AT/AT transition mutations were also observed (about 15% of all mutations in SOS-induced cells). Taken together, single and tandem GC-->AT mutations accounted for slightly over half (about 51%) of the mutations observed in SOS-induced cells. These results demonstrated that (+)anti-DB[a,j]A-DE was mutagenic in repair-proficient E. coli; however, unlike other polycyclic aromatic hydrocarbons that induce primarily transversion mutations, (+)anti-DB[a,j]A-DE caused mostly GC-->AT transitions.
Mol Carcinog 1993
PMID:Mutagenic specificity of the (+)anti-diol epoxide of dibenz[a,j]anthracene in the supF gene of an Escherichia coli plasmid. 821 33

Con8 mammary tumor cells are an epithelial cell line derived from the 7,12-dimethylbenz(alpha)anthracene-induced 13762NF rat mammary adenocarcinoma. The synthetic glucocorticoid dexamethasone suppresses the growth of Con8 cells, and after 5 days of treatment with this steroid, Con8 cells undergo less than 0.5 population doublings. This growth arrest is accompanied by a 30-fold elevation in c-jun transcript levels, no change in c-fos expression, and a moderate increase in total AP-1 transcriptional activity. Dexamethasone inhibited DNA synthesis within one cell cycle, and flow cytometry of propidium iodide-stained nuclei demonstrated that dexamethasone growth-suppressed cells had a DNA content indicative of a specific cell cycle block in either G1 or G0. Consistent with a G1/G0 arrest of the cell cycle, dexamethasone did not prevent Con8 cells from entering the S phase after release from synchronization at the G1/S boundary by a double thymidine block. Analysis of [3H]thymidine incorporation and autoradiography of [3H]thymidine-labeled nuclei revealed that after either dexamethasone withdrawal or the addition of transforming growth factor-alpha (TGF alpha), Con8 cells synchronously reinitiate cell cycle progression. Northern blot analysis demonstrated that an induction of transcripts for the G1 marker genes c-myc and cyclin D1 occurs before cells enter the S-phase. After dexamethasone withdrawal, c-myc and cyclin D1 expression transiently peak at 2 and 4 h, respectively. In contrast, c-myc expression peaked at 0.5-1 h, whereas cyclin D1 expression was induced at 2 h and maintained at a high level after the addition of TGF alpha. Our results demonstrate that glucocorticoids induce a specific block of the cell cycle progression of a rat mammary tumor cell, and that after synchronous progression through the cell cycle, the temporal expression pattern for c-myc and cyclin D1 is distinct for dexamethasone release vs. the addition of TGF alpha to glucocorticoid-suppressed cells.
Mol Endocrinol 1993 Sep
PMID:Glucocorticoids induce a G1/G0 cell cycle arrest of Con8 rat mammary tumor cells that is synchronously reversed by steroid withdrawal or addition of transforming growth factor-alpha. 824 14


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