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

7. CONCLUSIONS

Mouse mammary tumorigenesis caused by MMTV has provided a rich source of interesting genes that play a role in mammary development and tumorigenesis. Each stage of mammary tumorigenesis appears to result from the clonal out growth of cells containing additional integrated proviral MMTV genomes. Genes such as int1/wnt1, wnt3, wnt10B, int2/fgf3, fgf4, int3/notch, and int6 have been shown to be genetically altered in naturally formed mammary tumors as a consequence of MMTV integration. Although the role of the human homologs of all of these oncogenes in human breast cancer is still poorly understood, it is clear that this work has led to new understanding of the importance of these genes in mammary gland growth, development as well as tumorigenesis. The fact that fgf3/fgf4/hst from the int2 integration locus are frequently co-amplified in invasive ductal carcinomas of the breast clearly demonstrates the importance of these models in understanding the role of various genes in multistep process of breast tumorigenesis. Our 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 was the first demonstration of integration of MMTV in a cellular gene that plays a role in hormone-dependent breast cancers. The relevance of MMTV/int genes to human breast cancer have been studied. WNT10B expression has been detected in normal and benign porliferations of human breast tissue. Studies have also identified in breast cancer DNA a segment comprising LTR and env gene sequences, which were homologous to MMTV. It seems likely that some of the mutations induced by MMTV, and the signaling pathways in which the target genes take part, will be relevant to the progression from preneoplastic lesions to distant metastasis in human breast cancer. Further understanding of the functional role and their mechanisms of action could provide new insights into the importance of these genes in mammary and breast cancers.