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

6. RELEVANCE OF MAMMARY TUMOR VIRUS IN HUMAN BREAST CANCER

MMTV has been regarded as a potential model for human disease. Efforts to demonstrate the presence of viruses in human breast cancer through search for viral particles, immulogical cross-reactivity, or sequence homology have yielded contradictory results. Several lines of evidence, however, associate MMTV with human breast cancer. Detectable MMTV env gene-related antigenic reactivity has been found in tissue sections of human breast cancer (43-45), breast cancer cells in culture (46), human milk (47), in sera of patients (48), in cyst fluid (49), and in particles produced by a human carcinoma cell line (50). Sequence homology has also been found in human DNA under low stringency conditions of hybridization (51), and RNA related to MMTV has been detected in human breast cancer cells (52). The human homologue of the int-2 locus has been found to be amplified and expressed in 15% of the breast cancers (53-56). Our own studies involving hormone/carcinogen-induced mammary tumor model has provided interesting insights into the role of int5 novel MMTV integration and the nature of cellular gene involved in this integration locus. This is the first demonstration of integration of MMTV in a cellular gene that plays a role in hormone-dependent breast cancers. Wang et al (57) have detected mammary tumor virus env gene-like sequences in human breast cancer and suggest that these MMTV env gene-like sequences may play a role in the etiology of a large proportion of human breast cancer. Recent studies (58) have identified the human homologue of mouse wnt10b gene. The human WNT10B sequence was 88% and 95% identical to the murine gene at nucleotide and amino acid levels, respectively. In normal and benign proliferation of human breast tissue, WNT10B expression was found to be elevated in 3 of 50 primary breast carcinomas. These findings suggest that WNT10B gene may also be involved in human breast cancer, and show that there is differential expression of the WNT10B gene in benign and malignant disease. All the above studies clearly suggest that MMTV related genes may play a very improtant role in the etiology of human breast cancer. More detailed integrations may provide proof for definite role of MMTV in breast cancer.