Cell cycle basis for the onset and progression of c-Myc-induced, TGFalpha-enhanced mouse mammary gland carcinogenesis.
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.
Liao
D J
DJ
Vincent T Lombardi Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington DC 20007, USA.
Natarajan
G
G
Deming
S L
SL
Jamerson
M H
MH
Johnson
M
M
Chepko
G
G
Dickson
R B
RB
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019925:Cyclin A / Q000302:isolation & purification; D019938:Cyclin D1 / Q000302:isolation & purification; D056743:Cyclin D3; D019927:Cyclin E / Q000302:isolation & purification; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000302:isolation & purification; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004847:Epithelial Cells; D005260:Female; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000302:isolation & purification; D056465:Retinoblastoma-Binding Protein 1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000302:isolation & purification; D016211:Transforming Growth Factor alpha / Q000235:genetics*
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; C534697:Ccnd3 protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056743:Cyclin D3; D019927:Cyclin E; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases