Characterization of mammary plaques in DDD mice congenic for Mtv-2 gene, DDD/1-Mtv-2/Mtv-2.

Abstract

DDD/1 mice free from exogenous mouse mammary tumor virus (MMTV) do not develop any neoplastic mammary lesions. In GR mice, the expression of Mtv‐2, an endogenous proviral MMTV, leads to 100% incidence of mammary ductal hyperplasias and tumors. An Mtv‐2 congenic line, DDD/1‐Mtv‐2/Mtv‐2, was established by introducing Mtv‐2 from GR into DDD/1 to elucidate its function. Development of mammary plaques (MPQ) characterized by ductal hyperplasias was investigated in 152 congenic females on day 17 to 19 of the first pregnancy. The incidence of MPQ was 48.0% and most MPQ‐positive mice (75.3%) had only one MPQ. Generally, MPQ were small in size: the diameter was as small as ≦3 mm in 77.6% of them. Of 84 MPQ implanted into intact fat pads, 43 (51.2%), 38 (45.2%) and 3 (3.6%) showed undetectable, pregnancy‐dependent and autonomous growths; respectively when the hosts underwent pregnancy. Almost all MPQ produced normal‐appearing ductal‐alveolar outgrowths in mammary epithelium‐divested or cleared fat pads of virgins. MPQ implanted into cleared fat pads were very similar to normal mammary glands in the responses to progesterone (P) and estradiol (E) alone or in combination except for association of ductal hyperplasias in 4 of 12 MPQ under E+P treatment. These findings revealed the preneoplastic nature of MPQ. Exogenous MMTV proviruses were demonstrated in all MPQ. The int‐2 DNA rearrangement was found in 2 of 10 MPQ but in none of 9 mammary carcinomas and the int‐1 DNA rearrangement in none of 10 MPQ but in 5 of 10 carcinomas. It is thus likely that the Mtv‐2 gene participates in a very early stage of mammary tumorigenesis not directly but indirectly through insertion mutation of host genes, while the cellular oncogenes, int‐2 and int‐1, may contribute to preneoplastic transformation of mammary epithelium and progression from preneoplastic to more malignant states, respectively.