Identification of a proviral structure in human breast cancer

Involvement of a virus similar to mouse mammary tumor virus (MMTV) in human breast cancer has long been postulated but never demonstrated. We have det ected by PCR a 660-bp sequence similar to the env gene of MMTV but not to t he known endogenous viruses, in 38% of human breast cancers examined (Wang et al., Cancer Res., 55: 5173-5179, 1995), This sequence was expressed in 6 6% of the env-positive tumors as detected by reverse transcription-PCR (Wan g et al., Clin. Cancer Res., 4: 2565-2568, 1998). In this article we report the amplification of a whole proviral structure f rom each of two human breast carcinomas that were env positive. Using neste d extra-long PCR and primers from specific MMTV sequences, overlapping env- long terminal repeat (LTR), LTR-gag, gag-pol, and pot env segments were suc cessfully amplified. The 9.9-kb provirus is 95% homologous to MMTV but only 57% to human endogenous retrovirus K10 in 3.5 kb of the gag and pol genes. The provirus displays typical features of a replication competent virus, p lus the open reading frame for the superantigen and the glucocorticoid resp onsive element. Fluorescence in situ hybridization with a 2.7-kb env-LTR se quence of an env positive breast cancer cell line revealed that the sequenc e is inserted in several chromosomes but not in chromosomes from normal bre ast cells. The origin of the MMTV-like sequences is uncertain. Because they are undete ctable in normal tissues, because the similarity between the two isolates i s high (96%), and because they maintain open reading frames, they appear to be exogenous.