ROLE OF MMTV INTEGRATION LOCUS CELLULAR GENES IN BREAST CANCER

Rajeshwar Rao Tekmal, and Nagalakshmi Keshava

Department of Gynecology and Obstetrics and Winship Cancer Center, Emory University School of Medicine, Atlanta, GA 30322-4710, USA

Received 10/14/97 Accepted 10/17/97

4. FERAL MOUSE MODEL

MMTV has also been detected in feral strains of mice (41). Since these mice are hemizygous for endogenous MMTV, some fraction of the offspring lack endogenous MMTV genome. This makes it possible to unambiguously detect acquired MMTV genomes in mammary tumors. Even in this setting, wnt1/int1 and fgf3/int2 are activated by MMTV insertion at a frequency comparable to MMTV-infected low incidence mouse strains. The CZECH II mice lack endogenous MMTV genomes but do contain an infectious strain of MMTV that is transmitted congenitally through the milk. This colony has a 20% incidence of pregnancy-independent mammary adenocarcinomas that are histopathologically similar to those induced by MMTV (C3H). The frequency with which wnt1 was activated by MMTV was similar to that observed in BALB/cfC3H or CZECHII/C3H mammary tumors, whereas MMTV-induced activation of fgf3/int2 and fgf4 was significantly less frequent (2). Like high incidence inbred mouse strains, CZECH II mice also develop mammary preneoplastic HANs which has been developed into mammary hyperplastic outgrowth lines (HOGs; 2). The frequency of MMTV induced rearrangements of wnt1 is similar in both CZECHII HOGs and mammary tumors. It is predicted that in this setting, activation of wnt1 may be an early event in tumorigenesis which may disrupt regulatory controls of normal mammary gland development leading to lobular hyperplasia. It is also thought that the mammary tumors arising from within these HOGs frequently contain additional MMTV proviral genomes. Based on the results obtained (2) with the MMTV-infected wnt1 transgenic mice, it is possible that members of the fgf gene family to be activated by MMTV in tumors derived from wnt1 positive HOGs.