MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

Abstract

The study of the mouse mammary tumor virus (MMTV) has provided important insights into the mechanisms of gene transcription regulation by steroid hormones, the mode of action of heritable super antigens and the progressive nature of neoplastic transformation in the mammary gland. Here we describe the current situation with respect to the latter aspect of MMTV biology and the prospects for further advance in our understanding of breast cancer in humans that may be expected from a continued study of MMTV-induced mammary neoplasia. MMTV is a heritable somatic mutagen whose target range is limited. Commonly, the tumorigenic capacity of MMTV is restricted to mammary gland, whereas infection is found in a variety of cell types. In order to replicate, proviral DNA must be inserted into the cell DNA and cell division is required to ®x the mutation. Yet only in the mammary epithelium does this lead to neoplastic transformation. This suggests a unique relationship between MMTV and mammary epithelium. In evaluating this relationship, we and others have discovered genes and potential gene pathways that are pertinent in mammary di erentiation and neoplasia. In addition, the clonal nature of these progressive events from normal to malignant phenotype has become increasingly clear. The weight of these observations compel us to conclude that mammary neoplasms arise from multipotent mammary epithelial cells through a process of acquired mutations that are re¯ected in the increasingly malignant nature of the population of progeny produced by these damaged stem cells.

Impairment of mammary lobular development induced by expression of TGF?1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice

“…The data showed herein as well as elsewhere 25 indicates that, most probably, mammary cancers arise from partially differentiated, tissue specific progenitor cells. Interestingly, our results also show that in all the analyzed transgenic tumors, there is high expression at the WAP promoter (i.e., ectopic WAP-TGF␤1 transgene and endogenous WAP).…”

“…In a recent review article 25 it has been commented that MMTVinduced mammary tumors do not have to be preceded by premalignant lesions as plaques or HANs. We have found that MMTV-infected WAP-TGF␤1 transgenic animals show a significant reduction of premalignant lesions and a high incidence of WAP expresser tumors.…”

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

“…We speculate that ITAM-dependent signaling could cooperate with proviral integration next to cellular protooncogenes to provide additional 'hits' required for solid tumor formation. For example, tumorigenesis could be driven by ITAM signaling by Env and insertion of the proviral genome near Wnt or FGF family genes (Callahan and Smith, 2000). Similarly, the EBV LPM2A protein signals through other motifs in addition to the ITAM (Ikeda et al, 2000(Ikeda et al, , 2001Morrison and RaabTraub, 2005), and EBV encodes additional proteins such as LMP1 that contribute to transformation (ThorleyLawson, 2001).…”

Principles and practice of nucleosome positioningin vitro

“…The MMTV 5 LTR sits upstream of the viral genome and the promoter drives viral gene transcription, whereas the MMTV 3 LTR is adjacent to mouse genomic sequences and can influence proto-oncogene transcription (Richard-Foy and Hager 1987). In fact, most oncogenic effects are due to insertion of the LTR enhancers near a native promoter to induce inappropriate regulation (enhancer insertion), rather than driving transcription from the LTR promoter itself (promoter insertion) (Callahan and Smith 2000;Theodorou et al 2007).…”