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Common Integration Sites for MMTV in Viral Induced Mouse Mammary Tumors

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Abstract

The paradigm of mammary cancer induction by the mouse mammary tumor virus (MMTV) is used to illustrate the body of evidence that supports the hypothesis that mammary epithelial stem/progenitor cells represent targets for oncogenic transformation. It is argued that this is not a special case applicable only to MMTV-induced mammary cancer, because MMTV acts as an environmental mutagen producing random interruptions in the somatic DNA of infected cells by insertion of proviral DNA copies. In addition to disrupting the host genome, the proviral DNA also influences gene expression through its associated enhancer sequences over significant inter-genomic distances. Genes commonly affected by MMTV insertion in multiple individual tumors include, the Wnt, FGF, RSpo gene families as well as eIF3e and Notch4. All of these gene families are known to play essential roles in stem cell maintenance and behavior in a variety of organs. The MMTV-induced mutations accumulate in cells that are long-lived and possess the properties of stem cells, namely, self-renewal and the capacity to produce divergent epithelial progeny through asymmetric division. The evidence shows that epithelial cells with these properties are present in normal mammary glands, may be infected with MMTV, become transformed to produce epithelial hyperplasia through MMTV-induced mutagenesis and progress to frank mammary malignancy. Retroviral marking via MMTV proviral insertion demonstrates that this process progresses from a single mammary epithelial cell that possesses all of the features ascribed to tissue-specific stem cells.

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Abbreviations

MMTV:

mouse mammary tumor virus

HAN:

hyperplastic alveolar nodule

LRC:

label retaining cells

MLV:

murine leukemia virus

HOG:

hyperplastic outgrowth

Tcf:

T-cell factor

Lef:

lymphocyte enhancing factor

RTK:

receptor tyrosine kinase

ICD:

intracellular domain

CIS:

common integration site

RIS:

retroviral integration site

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Acknowledgement

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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  1. Mammary Gland Biology and Tumorigenesis Laboratory, National Cancer Institute, Building 37/Room 1118A, MSC4254, Bethesda, MD, 20892, USA

    Robert Callahan

  2. National Cancer Institute, Building 37/Room 1112A, MSC 4254, Bethesda, MD, 20892, USA

    Gilbert H. Smith

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Callahan, R., Smith, G.H. Common Integration Sites for MMTV in Viral Induced Mouse Mammary Tumors. J Mammary Gland Biol Neoplasia 13, 309–321 (2008). https://doi.org/10.1007/s10911-008-9092-6

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