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1.
Br J Cancer ; 91(7): 1372-9, 2004 Oct 04.
Article in English | MEDLINE | ID: mdl-15354213

ABSTRACT

The expression of the proto-oncogene c-myc is frequently deregulated, via multiple mechanisms, in human breast cancers. Deregulated expression of c-myc contributes to mammary epithelial cell transformation and is causally involved in mammary tumorigenesis in MMTV-c-myc transgenic mice. c-Myc is known to promote cellular proliferation, apoptosis, genomic instability and tumorigenesis in several distinct tissues, both in vivo and in vitro. Expression of the proapoptotic regulatory gene bax is reduced or absent in human breast cancers, and c-Myc has been shown to regulate the expression of Bax, as well as cooperate with Bax in controlling apoptosis in a fibroblast model. Additionally, loss of bax reduces c-Myc-induced apoptosis in lymphoid cells and increases c-Myc-mediated lymphomagenesis in vivo. In order to assess whether loss of bax could influence c-Myc-induced apoptosis and tumorigenesis in the mammary gland in vivo, we generated MMTV-c-myc transgenic mice in which neither, one, or both wild-type alleles of bax were eliminated. Haploid loss of bax in MMTV-c-myc transgenic mice resulted in significantly reduced mammary tumour apoptosis. As anticipated for an apoptosis-regulatory gene, loss of the wild-type bax alleles did not significantly alter cellular proliferation in either mammary adenocarcinomas or dysplastic mammary tissues. However, in contrast to c-Myc-mediated lymphomagenesis, loss of one or both alleles of bax in MMTV-c-myc transgenic mice did not significantly enhance mammary tumorigenesis, despite evidence that haploid loss of bax might modestly increase mammary tumour multiplicity. Our results demonstrate that Bax contributes significantly to c-Myc-induced apoptosis in mammary tumours. In addition, they suggest that in contrast to c-Myc-induced lymphomagenesis, mammary tumorigenesis induced by deregulated c-myc expression requires some amount of Bax expression.


Subject(s)
Apoptosis/genetics , Breast Neoplasms/genetics , Breast Neoplasms/physiopathology , Cell Division/genetics , Cell Transformation, Neoplastic , Mammary Neoplasms, Animal/genetics , Mammary Neoplasms, Animal/physiopathology , Membrane Proteins/genetics , Proto-Oncogene Proteins c-bcl-2 , Proto-Oncogene Proteins/genetics , Receptors, Virus/genetics , Animals , Blotting, Western , Disease Models, Animal , Down-Regulation , Genes, myc , Humans , Membrane Proteins/pharmacology , Mice , Mice, Knockout , Mice, Transgenic , Proto-Oncogene Mas , Proto-Oncogene Proteins/pharmacology , bcl-2-Associated X Protein
2.
Oncogene ; 19(8): 1065-71, 2000 Feb 21.
Article in English | MEDLINE | ID: mdl-10713691

ABSTRACT

Recent progress in the study of c-Myc has convincingly demonstrated that it possesses a dual role in regulating both proliferation and apoptosis; however, the manner in which c-Myc influences these cellular response pathways remains incompletely characterized. Deregulation of c-Myc expression, via many mechanisms, is a common feature of multiple cancers and is an especially prominent feature of many breast cancers. Of significant interest to those who study mammary gland development and neoplasia is the unresolved nature and contribution of apoptosis to breast tumorigenesis. Recently, the use of transgenic mice and gene-knockout mice has allowed investigators to evaluate the pathological mechanisms by which different genes influence tumor development and progression. In this review, we address two distinct c-myc-containing bitransgenic murine mammary tumor models and discuss the contribution and possible future directions for resolution of cancer-relevant molecular pathways influenced by c-Myc.


Subject(s)
Genes, myc , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Mice, Transgenic , Animals , Apoptosis/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Division/genetics , Female , Humans , Mice , Milk Proteins/genetics , Transforming Growth Factor alpha/genetics , Transforming Growth Factor alpha/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
3.
Oncogene ; 19(10): 1307-17, 2000 Mar 02.
Article in English | MEDLINE | ID: mdl-10713672

ABSTRACT

Using single and double transgenic mouse models, we investigated how c-Myc modulates the mammary epithelial cell cycle to induce cancer and how TGFalpha enhanced the process. In c-myc transgenic mice, c-myc expression was high in the hyperplastic mammary epithelium and in the majority of tumor areas. However, the tumors displayed focal areas of low expression of c-myc but high rates of proliferation. In contrast to E2F1 and cyclin A2, which were induced and co-localized with c-myc expression, induction of cyclins D1 and E occurred only in these tumor foci. Overexpression of cyclin D1 also occurred in the hyperplastic epithelium of tgfalpha-single and tgfalpha/c-myc-double transgenic mice. In tgfalpha/c-myc tumors, cells positive for cyclins D1 and E were randomly spread, without showing a reciprocal relationship to c-myc expression. In contrast to c-myc tumors, most tgfalpha/c-myc tumors showed undetectable levels of retinoblastoma protein (pRB), and the loss of pRB occurred in some cases at the mRNA level. These results suggest that E2F1 and cyclin A2 may be induced by c-Myc to mediate the onset of mammary cancer, whereas overexpression of cyclins D1 and E may occur later to facilitate tumor progression. TGFalpha may play its synergistic role, at least in part, by inducing cyclin D1 and facilitating the loss of pRB.


Subject(s)
Carrier Proteins , Cell Cycle Proteins , Cell Transformation, Neoplastic/genetics , DNA-Binding Proteins , Mammary Neoplasms, Experimental/genetics , Proto-Oncogene Proteins c-myc/genetics , Transforming Growth Factor alpha/genetics , Animals , Apoptosis , Cell Cycle/genetics , Cyclin A/isolation & purification , Cyclin D1/isolation & purification , Cyclin D3 , Cyclin E/isolation & purification , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclins/isolation & purification , E2F Transcription Factors , E2F1 Transcription Factor , Epithelial Cells , Female , In Situ Hybridization , In Situ Nick-End Labeling , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Transgenic , Models, Biological , Retinoblastoma Protein/isolation & purification , Retinoblastoma-Binding Protein 1 , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factor DP1 , Transcription Factors/isolation & purification
4.
Blood ; 91(7): 2443-51, 1998 Apr 01.
Article in English | MEDLINE | ID: mdl-9516144

ABSTRACT

Although Hodgkin's disease is highly responsive to treatments that cause apoptosis, it remains resistant to the physiological mechanisms intended to cause cell death. Presumably, the Reed-Sternberg cell defies endogenous apoptosis, persists, accumulates, and manifests the malignant disorder seen clinically. The Reed-Sternberg cell expresses several members of the tumor necrosis factor receptor superfamily. This family of receptors is involved in both activation and proliferation of cells, as well as either protection from or initiation of apoptosis in cells expressing these surface proteins. Signals from these receptors affect transcription. We reasoned that the activation state and resistance to apoptosis of Reed-Sternberg cells might be attributable to dysregulation of genes controling these processes. To determine gene expression by Reed-Sternberg cells, we developed a method of micromanipulation, global reverse transcription, and the reverse transcription-polymerase chain reaction and applied it to 51 single Reed-Sternberg cells and their variants from six cases of Hodgkin's disease. This report analyzes the gene expression of bcl-xs, bcl-xl, bax-alpha, bax-beta, fadd, fas, fas ligand (fas L), ice, TNF-alpha, TNF-beta, TNFR1, TNFR2, TRAF1, TRAF2, TRAF3, cIAP2, and tradd at the level of mRNA in the single Reed-Sternberg cells and their variants. The findings here suggest a molecular mechanism for the activated state and in vivo survival occurring in untreated Reed-Sternberg cells of Hodgkin's disease.


Subject(s)
Apoptosis/genetics , Gene Expression Regulation, Neoplastic , Hodgkin Disease/pathology , Reed-Sternberg Cells/pathology , DNA, Complementary/analysis , Humans , Polymerase Chain Reaction , Signal Transduction/genetics
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