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Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis

Oncogene volume 19, pages 1307–1317 (2000)Cite this article

Abstract

Using single and double transgenic mouse models, we investigated how c-Myc modulates the mammary epithelial cell cycle to induce cancer and how TGFα 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 tgfα-single and tgfα/c-myc-double transgenic mice. In tgfα/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 tgfα/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. TGFα may play its synergistic role, at least in part, by inducing cyclin D1 and facilitating the loss of pRB.

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Abbreviations

Cdk:

cyclin-dependent kinase

ER:

estrogen receptor

MMTV:

mouse mammary tumor virus

MT:

metallathionein

PCNA:

proliferating cell nuclear antigen

pRB:

retinoblastoma protein

TGFα:

transforming growth factor α

TUNEL:

terminal deoxynucleotidyl transferase nick end labeling

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Acknowledgements

We would like to express sincere gratitude to Dr W-H Lee, Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, TX, USA, for generously providing the antibody pRB245, to Mrs S Constable for helping in tissue processing, and to Dr E Rosfjord, J-K Wang, and Dr M-Z Dai for helping in preparing digital photos. This work was supported by NIH grants RO1 CA72460 and AG1496 to RB Dickson.

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Authors and Affiliations

  1. Vincent T Lombardi Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, 20007, DC, USA

    Dezhong J Liao, Geraldine Natarajan, Sandra L Deming, M Hunter Jamerson, Michael Johnson, Gloria Chepko & Robert B Dickson

  2. Department of Pathology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, 20007, DC, USA

    Michael Johnson

  3. The Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, 20007, DC, USA

    Michael Johnson & Robert B Dickson

  4. Department of Cell Biology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, 20007, DC, USA

    Robert B Dickson

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Liao, D., Natarajan, G., Deming, S. et al. Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis. Oncogene 19, 1307–1317 (2000). https://doi.org/10.1038/sj.onc.1203430

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