Mouse Mammary Tumor Virus Proviral Sequences Congenital to C3H/Sm Mice Are Differentially Hypomethylated in Chemically Induced, Virus-Induced, and Spontaneous Mammary Tumors

Drohan, William N.; Benade, Leonard E.; Graham, David E.; Smith, Gilbert H.

doi:10.1128/jvi.43.3.876-884.1982

Cited by 21 publications

(12 citation statements)

References 27 publications

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“…But whether it is a direct ultimate control mechanism or merely a consequence of long-term lack of expression remains unclear. DNA methylation has been implicated in eucaryotic gene expression (1,13,17,34), in control of MMTV expression (4), in tumorigenesis in mice (2,14,15), in human cancer (12,16,20), and in tumor progression to steroid insensitivity (6,21). Our data presented here lend further support to this latter hypothesis.…”

Section: Discussionsupporting

confidence: 78%

Progression to steroid autonomy in S115 mouse mammary tumor cells: role of DNA methylation.

Darbre¹,

King²

1984

The Journal of Cell Biology

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Although monoclonal in origin, mammary tumors acquire a marked heterogeneity of cell phenotypes, including a mixture of steroid hormone-sensitive cells and insensitive cells. We describe here long-term studies on the effects of androgen withdrawal on cloned androgen-responsive $115 mouse mammary tumor cells as a model system to investigate mechanisms by which tumor cells lose their steroid sensitivity. In the prolonged absence of androgen, the cells lost hormone-sensitive parameters reproducibly, including loss of proliferative response, saturation density response, cell morphology response, and mouse mammary tumor virus long terminal repeat (MMTV-LTR)-related RNA. These experiments have demonstrated that when deprived of hormone in the long term, a clone of responsive cells gives rise reproducibly to a population of unresponsive cells in an ordered series of phenotypic changes. At the time when the cells lost all androgen response in terms of cell biology and MMTV-LTR-RNA, increased methylation of MMTV-LTR sequences in the DNA was detected. Thereafter recovery of androgen sensitivity has not been achieved in any of these parameters. The possible role of de novo DNA methylation in the progression to androgen autonomy of $115 cells is discussed.Manipulation of the steroid environment affects breast tumor growth in many species (26, 29) but only on a temporary basis, and even in rodents, where effects are greatest, it never eliminates the tumor completely (19). In man, 30% of breast cancers regress after endocrine therapy, and a recent approach has been to select likely hormone-sensitive tumors on the basis of estrogen and progesterone receptor levels (9). However, possession of receptors is not the sole criterion for response to therapy and in any case regression is at best temporary, to be followed by hormone-independent tumors and metastatic disease. This progression to hormone insensitivity is a major clinical problem.Tumors are composed of mixed populations of cells that have a wide range of phenotypes. Cells obtained from individual rodent mammary tumors differ not only in hormone receptors (35) and hormone-dependent growth (8, 39) but also in immunological properties (24), transplantability (36), metastatic capability (18), tumorigenicity (38), drug resistance (23), growth rate (11), karyotype (11,22), mouse mammary tumor virus (MMTV) 1 expression (35), and MMTV proviral Abbreviations used in this paper. +A and -A, androgen responsive and unresponsive, respectively; DC, dextran-charcoal; DME, Dulbeccopies (32). It is now accepted that the origin of mammary tumors is monoclonal (10), but how such diversity arises is still unknown. The mechanism could involve either genotypic or phenotypic change. Evidence for a genotypic mechanism, involving mutation followed by cell selection, has been implied from karyotype studies (11,22,25) and from changes in exogenous integrated MMTV (32). A phenotypic mechanism would involve stable alteration in the program of gene expression and could result from either sele...

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Section: Discussionsupporting

confidence: 78%

Progression to steroid autonomy in S115 mouse mammary tumor cells: role of DNA methylation.

Darbre¹,

King²

1984

The Journal of Cell Biology

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“…The recent finding of MuMTV proviral amplification in some GR/A male mouse leukemias (23) is intriguing in this respect. Given the hypomethylated state of MuMTV proviruses in GR/A lymphoid tissue, the inadvertant transcription of these proviruses may result in MuMTV proviral amplification, a situation not unlike that found in mammary tumors (7,10,(12)(13)(14)17). Why this should occur only in male mice is unknown, but it may reflect a difference in the quantity or quality of various hormones.…”

Section: Discussionmentioning

confidence: 99%

“…All blots, unless otherwise noted, were probed with a mixture of cloned MuMTV PstI fragments (19) that had been labeled by nick translation (27). tissues (3,6,10,12,14). The normal tissue most commonly used has been liver, although kidney, heart, spleen, and mammary gland tissues have also been investigated.…”

Section: Methodsmentioning

confidence: 99%

“…Endogenous and acquired mouse mammary tumor virus (MuMTV) proviral DNA is less methylated in mammary tumors than the endogenous proviruses in mouse liver (3,6,10,12,14). Since MuMTV-specific RNA is easily detected in mammary tumors but not in livers (33), hypomethylation of MuMTV proviral DNA has been taken as prima facia evidence for MuMTV transcriptional activity (3,6,10,12,14).…”

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confidence: 99%

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Mouse mammary tumor virus: specific methylation patterns of proviral DNA in normal mouse tissues

Hu¹,

Fanning²,

Cardiff³

1984

J Virol

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The methylation state of endogenous mouse mammary tumor virus (MuMTV) proviral DNA was examined in normal mouse tissues. DNAs from various tissues were cleaved with the methylation-sensitive enzymes HhaI and HpaII and analyzed by Southern blotting. Tissue-specific MuMTV proviral DNA methylation patterns were found in the BALB/c, C3H, C57BL, GR/A, and GR-Mtv-2mouse strains. MuMTV proviral DNA was hypomethylated in DNAs from the spleens and testes of all strains examined. The GR/A mouse strain, which was most thoroughly studied, also showed hypomethylation of MuMTV proviral DNA in bone marrow and placental tissues. Analysis of RNAs extracted from GR/A liver, mammary tumor, testes, placenta, and spleen tissues demonstrated that MuMTV proviral hypomethylation need not reflect significant proviral transcription.

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“…(1981) have shown recently that Mtw-1 gene activity is linked to a single MMTV provirus which is detectable in Eco R, digests of C3H and DBA mouse DNA as a 4.5 kiiobare fragment. By comparison of the restriction analyses with those reported for various C3H sublines by Cohen and Varmus (1979), and our own studies (Drohan et al, 1982), it is clear that C3WSm (also designated C3WStWi) mice do not contain an EcoRl restriction fragment of this size. It must be assumed from this observation and the fact that C3WSm mammary tissues are routinely negative for MMTV antigens that C3WSm mice do not contain an active Mtv-1 locus.…”

Section: Discussionmentioning

confidence: 62%

Suppression of spontaneous mammary tumorigenesis despite mtv‐1 gene expression in hybrid and backcross c3h‐a^vyfb × c3h/sm mice

Smith

Henry

Vlahakis

et al. 1982

Intl Journal of Cancer

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Mouse mammary tumor virus (MMTV)-specific RNA and antigen content of normal and neoplastic mouse mammary tissue were measured in strains C3HISm and C3H-A"VB, in C3H-A"fBO X C3HISmdF, hybrids and in (C3H-A"WB X C3HISm) X C3H/Smi3 backcross segrewts. Good correlation between M M N antigen expression in lactating mammary glands and mammary tumor incidence was observed in the parental mouse strains. The high-mammary-cancer strain C3H-Av7fB (90 %) had consistently high levels of M M N antigen in the mammary glands and tumors, whereas mammary tissues from lowmammary-cancer subline C3HISm (1.6 %), whether normal or neoplastic, had little or no detectable MMTV antigen. In contrast, MMTV RNA content of normal C3HISm mammary tissue was consistently as high as or higher than corresponding levels in C3H-A"yfB females. These molecular data, along with the relative mammary tumor incidences, suggest that the endogenous MMTV provirus expression gene Mtv-l present in C3H mice is fully expressed in the C3H-A"VB subline but is silent or more probably absent in the C3H/Sm subline. Our earlier genetic crosses between C3H-A"yfB and C3H/Sm mice were conducted to determine the effect of the AvY gene on mammary tumorigenesis during its segregation in backcross (BC) females produced from matings of the F, hybrid females with C3HISm males. Our mammary tumor incidence data presented in the accompanying paper strongly suggested the possibility that C3H/Sm mice possessed a dominant genetic factor(s) which specifically attenuated the tumorigenic effects of the A " y and M&-/ genes on the mammary gland without affecting the A' Y gene's enhancement of liver tumorigenesis and obesity.Examination of MMTV RNA and antigen content in (C3H-AVfB X C3H/Sm) hybrid and BC females showed that the expression of MMTV antigen was completely suppressed in the agouti (AA) BC females. However, yellow F, (A'YA) and yellow (A"YA) BC females continued to express MMTV antigen in their mammary glands even though mammary tumor incidence was significantly depressed.MMTV RNA levels were similar in all F, and BC females regardless of the presence or absence of the A"Y gene.Mammary tumor incidence was reduced in all the BC females (whose genome is 3/4 derived from C3HISm) relative to the F, females (whose genome is only 112 derived from C3H/Sm) suggesting that more than one gene is involved in the suppression of spontaneous mammary tumor development. Cessation of translational expression of endogenous MMTV occurred only in the agouti (An) BC females, suggesting an association between this phenomenon and the agouti locus of C3HISm. Evaluation of the relative M M N RNA content of nucleic and cytoplasmic fractions from C3HISm mammary tissues strongly suggests that transport andlor processing of MMTV RNA is defective in these mice. This defect probably accounts for the absence of detectable M M N antigens in C3HISm and agouti (AA ) BC mammary tissues and tumors and may contribute to the observed reduction in mammary tumor incidence.Various genes specifying resistance to andlo...

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Mouse Mammary Tumor Virus Proviral Sequences Congenital to C3H/Sm Mice Are Differentially Hypomethylated in Chemically Induced, Virus-Induced, and Spontaneous Mammary Tumors

Cited by 21 publications

References 27 publications

Progression to steroid autonomy in S115 mouse mammary tumor cells: role of DNA methylation.

Progression to steroid autonomy in S115 mouse mammary tumor cells: role of DNA methylation.

Mouse mammary tumor virus: specific methylation patterns of proviral DNA in normal mouse tissues

Suppression of spontaneous mammary tumorigenesis despite mtv‐1 gene expression in hybrid and backcross c3h‐a^vyfb × c3h/sm mice

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Mouse Mammary Tumor Virus Proviral Sequences Congenital to C3H/Sm Mice Are Differentially Hypomethylated in Chemically Induced, Virus-Induced, and Spontaneous Mammary Tumors

Cited by 21 publications

References 27 publications

Progression to steroid autonomy in S115 mouse mammary tumor cells: role of DNA methylation.

Progression to steroid autonomy in S115 mouse mammary tumor cells: role of DNA methylation.

Mouse mammary tumor virus: specific methylation patterns of proviral DNA in normal mouse tissues

Suppression of spontaneous mammary tumorigenesis despite mtv‐1 gene expression in hybrid and backcross c3h‐avyfb × c3h/sm mice

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Suppression of spontaneous mammary tumorigenesis despite mtv‐1 gene expression in hybrid and backcross c3h‐a^vyfb × c3h/sm mice